ACP medicine, 3rd Edition

Infectious Disease

Human Retroviral Infections other than HIV Infection

Mark A. Beilke MD¹

Professor and Chief

Christy Barrios PHD²

¹Division of Infectious Diseases, Medical College of Wisconsin

²Medical College of Wisconsin

The authors have no commercial relationships with manufacturers of products or providers of services discussed in this chapter.

July 2007

Retroviruses derive their name from the action of a unique enzyme called reverse transcriptase. The normal flow of genetic information is from DNA to RNA to protein; in a reversal of that process, reverse transcriptase makes a double-stranded DNA copy (complementary DNA [cDNA]) of the single-stranded viral RNA genome.¹ The newly created viral DNA then becomes integrated into the genome of the infected host cell.

Retroviruses other than HIV are associated with hematologic, neurodegenerative, and possibly autoimmune disease. Acquisition of retroviruses may be exogenous or endogenous. Exogenous acquisition, as with HIV, occurs through direct contact with infected persons or their bodily fluids; endogenous retroviruses are transmitted along with host genetic information contained in the germ cell.

In addition to HIV, the human retroviruses with the most clearly defined roles in clinical disease are the human T cell lymphotropic virus types I and II (HTLV-1 and HTLV-2). HTLV-1 causes adult T cell leukemia/lymphoma (ATL), T cell non-Hodgkin lymphoma, and an unusual neurodegenerative syndrome designated tropical spastic paraparesis or HTLV-1-associated myelopathy (TSP/HAM). HTLV-2 causes large granular cell leukemia (CD8⁺), CD8⁺ cutaneous lymphoma, and T cell variant hairy cell leukemia²; it may increase the risk of certain infectious diseases and rarely causes TSP/HAM.

Recently, viruses closely related to HTLV-1 and HTLV-2 have been detected by serologic studies conducted in Cameroon, Africa.^3,4 These viruses, designated HTLV-3 and HTLV-4, have yet to be linked to disease, but because of difficulties conducting studies in remote areas of Africa, it is premature to draw any conclusions.

Human endogenous retroviruses may have a role in the pathogenesis of autoimmune diseases.^5,6 Although replication of endogenous retroviruses within their host cells is highly restricted, induction of replication in vitro is observed when the host cells are activated by a chemical stimulus.⁷ The link between human endogenous retroviruses and clinical disease remains speculative, however.

Human foamy viruses (HFVs) have been extensively investigated as causes of disease. However, very little evidence exists to suggest a pathogenic role.^8,9,10

During the 1990s, there was concern that a new retrovirus might have been identified in HIV-1-seronegative patients presenting with an AIDS-like illness. These patients were classified as having idiopathic CD4⁺ T lymphocytopenia.^11,12 Human intracisternal retroviral particles have been identified in lymphoid cultures established from these patients¹³; a causal link has not been conclusively established, however, because retroviral infection cannot be documented in all affected patients.

Epidemiology of HTLV-1 and HTLV-2 Infections

The human retroviruses have been shown to be phylogenetically related to the retroviruses of Old World primates. The closest viral relative of HTLV-1 is the simian T cell lymphotropic virus type I, which was identified as an agent of naturally occurring infection in many species of Old World monkeys and great apes. Antecedent infection of the human population probably occurred from three geographically distinct interspecies transmission events; once established, the virus followed the migratory patterns of people around the world.¹⁴ The likelihood of primate-to-human transmission of HTLV-1 is supported by studies demonstrating the passage of simian immunodeficiency virus from chimpanzees to humans and its transformation into HIV.¹⁵

HTLV-1 has a worldwide distribution [see Figure 1]. The prevalence ranges from 5% to 27%; higher rates occur in endemic areas such as southwestern Japan and Okinawa, where more than one million persons are infected. HTLV-1 infection is also prevalent in Taiwan; the Caribbean basin, including areas of South America and the southeastern United States; central Africa; Israel; and the Arctic, where seroprevalence rates range from 5% to 27% in adults.¹⁶

Figure 1. Worldwide distribution of human T cell lymphotropic virus types 1 and 2 (HTLV-1 and HTLV-2) infections.114,177,178,179,180 HTLV-1 infection occurs primarily in geographic locations where the virus is endemic, with sporadic infection elsewhere as a result of immigration or spread through injection drug use. In contrast, HTLV-2 infections occur not only within endogenous populations but are also spread in epidemic proportions among injection drug users in large metropolitan regions in the Americas and Europe. Note that HTLV-2 has four molecular subtypes (a–d).

HTLV-2 is endemic in several Native American populations and in Pygmy tribes in central Africa; in these populations, the prevalence ranges from 7% to 9%.¹⁷ In the United States, the seroprevalence of HTLV-1 and HTLV-2 ranges from 7% to 49% in injection drug users and prostitutes.¹⁶ Early serologic and epidemiologic studies were unable to effectively differentiate between HTLV-1 and HTLV-2; however, this problem has been solved through the use of more specific serologic assays.¹⁷ Such assays have shown that the majority of HTLV infections in injection drug users are caused by HTLV-2.¹⁸

In the United States, the seroprevalence of HTLV-1 and HTLV-2 in blood donors is 0.025%.¹⁶ The annual HTLV-1/2 seroconversion rate is estimated to be 1.09 per 100,000 population.¹⁹ Because donated blood in the United States is screened for HTLV-1 and HTLV-2, the risk of transmitting such infection through a unit of blood is estimated to be 1 in 641,000 (95% confidence interval, 256,000 to 2,000,000).¹⁹ More common transmission routes for HTLV-1 infection are from mother to child during pregnancy, perinatally, or through breast milk; through sexual contact; and through contaminated needles.²⁰

The distribution of ATL and TSP/HAM overlaps the distribution of HTLV-1, with more than 95% of affected persons having serologic evidence of HTLV-1 infection. The development of ATL in persons infected through the use of blood products is rare; however, 20% of patients with TSP/HAM acquire HTLV-1 from contaminated blood.

Biology of Retroviruses

Physical Structure and Genomic Organization

All human retroviruses share several similarities with respect to their structure, genomic organization, and mode of replication.²¹Structurally, retroviruses are categorized as types A, B, C, or D, on the basis of their shape and where particle maturation takes place within the host cell.^22,23,24 The cores of type C viruses (such as HTLV-1 and HTLV-2) are characterized by two concentric shells that have a double-ring appearance in specimens prepared for electron microscopy²⁵ [see Figure 2]. In contrast, endogenous retroviruses, which are type A particles, are smaller (70 nm) and are seen only intracellularly.²⁶ Type C viruses assemble their capsid and mature at the plasma membrane of infected cells during the budding process. No intracellular precursor is seen.²⁷

Figure 2. Electron micrograph of HTLV-1 virions budding from cultured lymphocytes obtained from an HTLV-1-infected patient. HTLV-1 virions contain a central, round nucleocapsid characteristic of type C retroviruses. HTLV-1 virions are never identified in uncultured cells or tissues of HTLV-1-infected individuals.

HTLV-1 and HTLV-2 differ from HIV-1 with respect to morphology and genomic structure [see Table 1].^28,29 HTLV virus particles are approximately 100 nm in diameter and have a lipid envelope that includes components of the host cell plasma membrane.³⁰ The lipid envelope surrounds a dense nucleocapsid core that contains two copies of the single-stranded RNA genome.

Table 1 Morphologic and Structural Characteristics of HIV-1 versus HTLV-1 and HTLV-227,28

Characteristic HIV-1 HTLV-1/HTLV-2 Taxonomy Lentivirus Oncornaviruses Morphology Bullet-shaped nucleocapsid, 100–120 nm in diameter Round nucleocapsid, 100 nm in diameter Visions detected in biopsy samples by electron microscopy Yes No Structural genes (products) gag (p17, p24, p2, p7, p1, p6) gag (p19, p24, p15) pol (reverse transcriptase, integrase, protease) pro (protease) env (gp120, gp41) pol (reverse transcriptase, possibly integrase)   env (gp46, p21) Accessory genes (products and functions) vif (virion infectivity protein)   vpr (viral protein R; enhances viral replication) tax (transcriptional activator) tat (viral trans-activator) rex (posttranscriptional modification) rev (regulator of expression of viral protein) Other accessory genes may exist, but their function is unknown vpu (viral protein U; enhances virion release from cell)   nef (negative regulatory factor)

The retroviral genome contains both noncoding and coding sequences. The noncoding sequences, which are important recognition sites for DNA or RNA synthesis, integration, and polyadenylation, are located at the 5′ and 3′ terminal ends of the genome. All retroviruses are terminally redundant and contain identical sequences called long terminal repeats (LTRs). The coding sequences include the gag gene, which encodes group-specific structural antigens; the pol gene, which encodes RNA-dependent DNA polymerase or reverse transcriptase, integrase, and protease; and the env gene, which encodes envelope structural proteins. The gag gene encodes a precursor polypeptide that is cleaved by viral-encoded protease to form several internal structural proteins—namely, matrix protein, capsid protein, and nucleic acid-binding protein.²¹

The HTLV genome is highly conserved, but greater nucleotide convergence in the LTRs has made possible the development of restriction fragment length polymorphism (RFLP) testing. RFLP testing has enabled researchers to classify both HTLV-1 and HTLV-2 into genotypic subtypes, which has yielded valuable information on viral transmission.³¹ There are five major molecular and geographic subtypes of HTLV-1: cosmopolitan (worldwide), Japanese, West African, Central African, and Melanesian.³² There are three HTLV-2 subtypes, which reflect population clustering rather than geographic clustering: a, b, and c. Subtype a is found in injection drug users worldwide, subtype b is found primarily in Native Americans, and subtype c is found in Brazilian tribes.³³

HTLV-1 and HTLV-2 have similar genomes, and approximately 60% of their nucleotides are the same. The gag gene encodes for the structural proteins p19, p24, and p15. The pol gene encodes for the protease and the reverse transcriptase. The env gene encodes for the external envelope and transmembrane glycoproteins gp46 and gp21. The spliced regulatory proteins tax and rex and the other three open reading frames constitute the 9 kb genome. The gag and env proteins are most immunogenic; antibodies to these proteins are commonly detected by enzyme immunoassay (EIA) and Western blot assay.

Cellular Tropism and Viral Entry

Transmission of retroviruses to humans requires parenteral or intimate mucous membrane exposure to the virus. Transmission by fomites is unlikely because once retroviruses are outside the body, their lipid envelope is easily damaged by exposure to high temperatures, detergents, and chemical disinfectants and through drying. Unlike HIV-1, the HTLV viruses are highly cell associated. Therefore, transmission through contact with cell-free fluids such as plasma occurs extremely rarely, if at all. HTLV-1 and HTLV-2 (like HIV-1) are transmitted through genital fluids; through blood (via transfusion, organ transplantation, or contaminated needles); or from mother to child via breast milk, in which HTLV-1-infected CD4⁺ T cells are abundant. Rare cases of in utero transmission have been reported.

HTLV-1 preferentially infects T cells, primarily CD4⁺ T cells.³⁴ HTLV-2 appears to preferentially infect CD8⁺ T cells, but the integrated viral cDNA is also detected in CD4⁺ T cells.^35,36 However, entry of HTLV-1 or HTLV-2 into CD4⁺ and CD8⁺ T cells does not appear to require the CD4 or CD8 receptor. Both HTLV-1 and HTLV-2 share tropism for a variety of nonlymphoid cells, suggesting the possibility that these viruses utilize a more ubiquitous cellular receptor for host cell binding and entry.^37,38 At least one laboratory has presented evidence suggesting that nearly all mammalian cell lines express a functional HTLV envelope receptor; interestingly, the receptor may be underexpressed (or perhaps absent) on human resting T cells and is expressed only upon T cell activation.³⁹ HTLV-1 and HTLV-2 may enter T cells via different receptor complexes⁴⁰; however, receptor-mediated entry may well be unnecessary for these viruses to infect T cells. HTLV-1 may spread between lymphocytes without actual budding from the donor cell.^41,42 Instead, the virus may transfer through cell-cell contact.

Except in cases of blood-borne transmission, initial infection with HTLV-1 or HTLV-2 occurs locally, within the regional lymphatics. Trafficking of HTLV-1-infected cells via lymphatics and the bloodstream may result in dissemination of the virus to various reservoirs of infection, including the skin, thymus, liver, spleen, mucosa-associated lymphoid tissue, and perivascular locations within the central and peripheral nervous systems.

Efficient replication of HTLV-1 and HTLV-2 within their respective target cells follows the paradigm of mammalian retroviruses.²⁰ After the virus enters the T cell, the single-stranded viral RNA is copied into an RNA/DNA hybrid by the viral reverse transcriptase enzyme. The RNA template is then degraded and the reverse transcriptase copies the single-stranded DNA into a double-stranded DNA-DNA hybrid through multiple steps. The full-length, double-stranded DNA then either circularizes and exists in a nonintegrated episomal form or is transported into the cell nucleus and becomes integrated within the host genome at random sites.⁴³

Integration and Latency

A defining feature of retroviruses is the integration of the reverse-transcribed viral cDNA into the genome of the host cell. The cDNA integrates permanently at a single random site in the cell chromosome. The integration of linear viral cDNA occurs during division of the cell; as such, nondividing cells are generally resistant to retroviral infection.

The integrated viral cDNA is termed the provirus; it serves as the template for viral replication. This process of integration may result in persistent infection or malignant transformation of the infected cell. Although many retroviruses can cause cytopathology in the host cell, most replicate without killing the infected cell. For the endogenous human retroviruses (human endogenous retrovirus type K [HERV-K], HERV-W, and several others), multiple copies of endogenous proviral DNA sequences are integrated into chromosomal DNA and are transmitted in the germ line. Interestingly, endogenous proviral sequences represent 0.1% or more of human DNA sequences and apparently were acquired sometime in our evolutionary past.²¹

Integration of human retroviruses differs from that of certain animal retroviruses in that no transforming genes (oncogenes) are associated with the viral genome, and the proviral genome is not regularly inserted next to a host-transforming gene. Moreover, clinically important human retroviruses are exogenous and are not transmitted in germ cells, as are some endogenous vertebrate retroviruses and the clinically unimportant HERVs.

In contrast to HIV, which is cytopathic for CD4⁺ T cells, both HTLV-1 and HTLV-2 immortalize primary human peripheral blood T cells in vitro. Immortalization is defined as interleukin-2 (IL-2)-dependent, long-term growth in culture [see Figure 3]. Subsequently, the cells become fully transformed, and can proliferate continuously in the absence of IL-2. Cellular transformation is an early step in the pathogenic process of HTLV and is distinct from oncogenesis or malignancy.²¹ HTLV transformation of T cells results in a pool of proliferating cells that are not oncogenic themselves but that provide a population from which a malignant clone may subsequently arise.²¹ This accounts for the long latent period between infection and tumor development in HTLV disease.

Figure 3. Immunofluorescence micrograph of an interleukin 2-dependent, HTLV-1-producing cell line established from the peripheral blood mononuclear cells of a patient with tropical spastic paraparesis/HTLV-1-associated myelopathy. The green staining represents expression of HTLV-1 p19 core antigen; cells are counterstained with Evan's blue, which appears orange.

Viral Transcription and Regulation of Gene Expression

After integration of the retroviral genome into host DNA, a second replication phase begins with the production of viral genomic RNA and messenger RNA (mRNA) and protein synthesis. The production of mRNA and protein synthesis occur almost exclusively through the enzymatic machinery of the host cell under the influence of viral gene regulatory products. The processing of virion proteins begins in the endoplasmic reticulum and Golgi complex. Virion assembly initiates at the plasma membrane, and the nascent virions are released from the cell surface through budding. The budding viral envelope, which has a phospholipid composition different from that of the plasma membrane of the cell, may incorporate some cell membrane surface proteins, along with virus-specific glycoproteins.^30,44

The complexity of the human retroviruses is best exemplified by the array of viral proteins that are responsible for regulating viral replication and the host cell response to infection.^21,45 HTLV-1 has a region between the env gene and the 3′ LTR that encodes for two regulatory proteins, tax and rex, which are produced from messages that are spliced differently from distinct overlapping reading frames. The tax protein induces the expression of cell transcription factors that alter host cell gene expression, and the rex protein regulates the expression of viral mRNA.

Tax has been implicated as the transforming protein of HTLV-1 and is centrally involved in the complex steps of leukemogenesis after years of subclinical infection. Although other transforming retroviruses contain oncogenes such as src (Rous sarcoma virus), myb (avian myeloblastosis virus) and erbA/erbB (avian erythroblastosis virus), which have a cellular counterpart or integrate into the host genome and upregulate downstream protooncogenes and other growth-promoting genes, HTLV-1 does not appear to follow either mechanism of transformation.⁴⁵ Tax has a variety of functions, including constitutive activation of transcription factors, modification of signal transduction pathways, alteration of tumor suppressor protein functions, modulation of cell cycle checkpoint proteins, interference with DNA repair, and inhibition of apoptosis. Tax induces the expression of a wide range of host cell proteins, including transcription factors and cytokines (e.g., IL-2 and tumor necrosis factor [TNF]) [see Table 2]. How this induction of host cell factors leads to neoplastic transformation remains unknown, however, and no consistent chromosomal abnormalities have been reported in ATL. The discordant observations between the in vitro and in vivo milieus are a recurrent theme in understanding the complex biology of human retroviral disease.

Table 2 Principal Cellular Genes That Are trans-Activated by HTLV-1 Tax Protein

Gene Products Effect on Activity Pathophysiologic Consequence Cytokines and receptors Upregulation Polyclonal expansion of infected cells IL-1 IL-2 and IL-2Rα GM-CSF IL-6 IL-8 IL-10 IL-13 IL-15 TNF-β MIP-1α, MIP-1β Host transcription factors (c-fos c-sis, c-rel, c-myc, erg-1, erg-2, fra-1) Upregulation Cellular transformation Adhesion molecules (ICAM-1, vimentin, CD54) Upregulation Lymphocyte tracking into involved tissues Pro-apoprotic factors (bax, p53) Downregulation Cellular transformation and leukemogenesis DNA repair enzymes Downregulation Cellular transformation and leukemogenesis GM-CSF—granulocyte-macrophage colony-stimulating factor   ICAM—intercellular adhesion molecule   IL—interleukin   MIP—major intrinsic protein   TNF—tumor necrosis factor

Host Immune Responses to Infection

Infection with HTLV-1 and HTLV-2 typically evokes a robust host humoral and cellular immune response.⁴⁶ Nevertheless, these viruses are able to evade destruction through their ability to integrate into the host genome and propagate during the normal physiologic process of cellular division, as well as their ability to spread directly from cell to cell, without production of extracellular virions.^42,46

Infection with HTLV-1 results in the development of antibodies within 1 to 2 months, after which levels of antibody persist at a stable level for life.⁴⁷ Proviral nucleic acid sequences can be detected during the window phase before seroconversion. Clinical disease manifestations correlate fairly closely with antibody titers and proviral load.⁴⁸ Patients who develop TSP/HAM appear to mount the most robust humoral immune responses [see Figure 4], followed by patients with pre-ATL; asymptomatic carriers generally exhibit lower antibody titers and lower levels of HTLV proviral burden.^49,50 Viral neutralizing antibodies directed at epitopes within the envelope region can be detected in asymptomatic carriers of HTLV-1, but these antibodies do not appear to be protective.^49,50 Nonetheless, the potential for protection against infection via induction of viral neutralizing antibodies by HTLV-1 vaccines is under investigation.^51,52

Figure 4. Western blots of Colombian patients with tropical spastic paraparesis/HTLV-1-associated myelopathy, and their spouses. Note robust humoral immune response with serum reactivity to all the major HTLV-1 polypeptides. Patient number 22 is HTLV-1 negative but HIV-1 positive.

Both HTLV-1 and HTLV-2 infections are associated with spontaneous proliferative responses in vitro, which can be observed early in the course of infection.^34,53 HTLV-1-infected CD4⁺ T cell lines induce the proliferation of CD4⁺ T cells.⁵³ It has been suggested that this inducing of the proliferation of CD4⁺ T cells is a mechanism for the spread of HTLV-1 infection, inasmuch as these newly recruited CD4⁺ T cells become additional targets for the HTLV-1 virus.³⁴

HTLV-1-specific CD4⁺ T cells respond in vitro to HTLV-1-infected targets, and these responses appear more robust in patients with TSP/HAM.³⁴ Cellular cytotoxic immune responses appear to be strong and persistent in persons infected with HTLV-1.⁵⁴ HTLV-1-specific cytotoxic T lymphocytes (CTLs) control HTLV viral burden by eliminating HTLV-1-infected CD4⁺ T cells. Despite the documented high frequency of HTLV-1-specific CTLs, CTLs are ineffective in eradicating the entire viral reservoir. In fact, CTL activity appears to contribute directly to the development of disease, especially TSP/HAM.^55,56 Expansion of CTL clones that are specific for HTLV-1-tax is pathognomonic of TSP/HAM and is strongly restricted to specific human leukocyte antigen (HLA) alleles.⁵⁷ Indeed, the HLA status of an HTLV-1-infected person may be an important factor in determining whether the infection leads to ATL or to TSP/HAM; in one study, specific HLA alleles (i.e., HLA-A*26, B*4002, B*4006, and B*4801) were found at significantly higher frequencies in ATL patients than in TSP/HAM patients and asymptomatic HTLV-1 carriers.⁵⁸

In contrast to patients with TSP/HAM, patients with ATL or smoldering ATL appear to have a diminished HTLV-1-specific CTL response.⁵⁹ This may be in part explained by downregulation of HTLV-1 tax expression in ATL cells or by mutation of the tax gene.^60,61 A proof-in-concept of this hypothesis was demonstrated in a rat model of ATL, in which adoptively transferred T cells from donors immunized with a DNA-taxvaccine replenished HTLV-1 tax-specific CTL responses and prevented the development of ATL.⁶²

Clinical Aspects of Infection

Like other viruses, retroviruses may cause latent, chronic, or persistent infections.⁶³ Latent infection is characterized by intermittent episodes of acute or subclinical disease; between episodes, no virus is detectable. In chronic infection, the virus is usually demonstrable but symptoms of disease are absent. Persistent infection is characterized by a long incubation period with slowly increasing amounts of virus, eventually leading to symptomatic disease. Clinical disease develops in only 5% to 10% of persons infected with HTLV-1 or HTLV-2. In ATL, the latent period between infection and the emergence of disease lasts 20 to 30 years or more. TSP/HAM has a median latency period of approximately 3 years, but the latency period can be as long as 20 to 30 years. Clinical manifestations of HTLV infection include malignancies, neurologic disorders, autoimmune disorders, and increased susceptibility to certain other infectious diseases [see Table 3].

Table 3 Clinical Manifestations of HTLV-1 and HTLV-2 Infections

Manifestation HTLV-1 HTLV-2 Malignancies Chronic ATL Large granular cell leukemia (CD+) Smoldering ATL CD8+ cutaneous lymphoma T cell non-Hodgkin lymphoma T cell variant hairy cell leukemia Neurologic manifestations TSP/HAM TSP/HAM   Peripheral neuropathy Autoimmune disorders Polymyositis Hashimoto thyroiditis Arthritis Uveitis Thyroiditis Pneumonitis Infectious diseases Opportunistic infections in ATL patients* Bacterial pneumonia Infective dermatitis in children Tuberculosis Strongyloides stercoralis infections Urinary tract infections ATL—adult T cell leukemia/lymphoma   TSP/HAM—tropical spastic paraparesis or HTLV-1-associated myelopathy *Opportunistic infections may include cytomegalovirus pneumonitis, Pneumocystis jiroveci pneumonia, disseminated herpes zoster, aspergillosis, cryptococcosis, disseminated Mycobacterium aviuminfection, and miliary tuberculosis.

HTLV-1

HTLV-1 is the etiologic agent of ATL and TSP/HAM. This virus has also been implicated in several other disorders, including an inflammatory arthropathy, uveitis, polymyositis, Sjögren syndrome, pulmonary disorders, and infectious dermatitis in children. There are provocative but unproven associations of HTLV-1 with mycosis fungoides and Sézary syndrome. This discussion focuses on ATL and HAM because of the established etiologic linkage to HTLV-1.

Pathophysiology

The pathophysiologic basis of HTLV-1 disease is less well known than that of HIV-1. Unlike HIV-1, the cellular receptor for HTLV-1 has not been identified. CD4⁺ T cells are productively infected by HTLV-1, but some other cell types, including B cells and CD8⁺ T cells, are infected occasionally. Like HIV-1, the reverse-transcribed viral cDNA integrates randomly into the host cell to establish the provirus, but in contrast to HIV-1, HTLV-1 establishes a latent infection with infrequent expression of viral gene products. As such, HTLV-1 has a very low level of disease penetrance; the transformation of an infected cell is a rare event, and the cumulative lifetime risk of developing ATL is only 1% to 5% in persons infected with HTLV-1. The latency period from infection to clinical disease is estimated to be 30 to 50 years⁶⁴; most persons with ATL appear to have acquired the infection in childhood.⁶⁵

HTLV-1-Induced Adult T Cell Leukemia/Lymphoma

Four clinical presentations of ATL have been described: acute, lymphomatous, chronic, and smoldering.⁶⁴ All of these malignancies are characterized by the monoclonal expansion of CD4⁺ T cells that contain HTLV-1 provirus and rearrangements of clonal T cell receptor genes. HTLV-1 virions are not recovered directly from the infected T cells, but viral tax protein is expressed in vivo. The molecular pathogenesis of this retrovirus-induced neoplasm has not been fully elucidated.

Acute ATL

Acute ATL accounts for approximately 60% to 80% of ATL cases. Patients experience a short clinical prodrome, with an average of 2 weeks between the onset of symptoms and diagnosis. ATL has an aggressive natural history; median survival is 6 months. The clinical picture is characterized by rapidly progressive skin lesions (occurring in 40% of cases and ranging from maculopapular rashes to tumorous lesions), pulmonary infiltrates, diarrhea, hypercalcemia (seen in 50% of cases), elevated lactate dehydrogenase (LDH) and alkaline phosphatase levels, and lymphocytosis with pleomorphic mononuclear cells (termed flower cells) that contain lobulated, cloven-hoof-shaped nuclei [seeFigure 5]. The skin lesions may be difficult to distinguish from those of mycosis fungoides and Sézary syndrome [see Figure 6]. The pulmonary lesions may be the result of a leukemic infiltrate or an opportunistic infection, such as from Pneumocystis jiroveci or a fungus. Diarrhea is almost always associated with an opportunistic infection. Hepatosplenomegaly may be present. Lytic bone lesions are common; the lesions are patchy and are composed of osteolytic cells without osteoblastic activity. Leptomeningeal involvement, with weakness, altered mental status, paresthesias, and headache, occurs in approximately 10% of patients. The cerebrospinal fluid protein level is usually normal. The diagnosis is confirmed by a finding of malignant cells in the CSF.

Figure 5. Peripheral blood smear in ATL. ATL cells (sometimes described as flower cells) appear pleomorphic and multilobulated and have significant nuclear convolutions.

Figure 6. Cutaneous involvement in ATL. Lesions are generalized, nodular, and indurated.

Lymphomatous ATL

Lymphomatous ATL accounts for approximately 20% of cases of ATL. Lymphomatous ATL is similar to acute ATL, except for the presence of lymphadenopathy and the absence of morphologically abnormal lymphocytes in the circulation. The diagnosis may be suspected on the basis of the patient's geographic birthplace and the presence of skin lesions and hypercalcemia. The diagnosis is confirmed by HTLV-1 serologic testing or the detection of the integrated provirus on polymerase chain reaction (PCR) testing.

Chronic ATL

Chronic ATL accounts for approximately 15% of cases of ATL. This form of ATL is characterized by normal serum levels of calcium, elevated levels of LDH, and the absence of bony involvement or involvement of the central nervous system or gastrointestinal tract. The median survival for these patients is 2 years. Chronic ATL may progress to acute ATL.

Smoldering ATL

In smoldering ATL, which accounts for fewer than 5% of cases of ATL, fewer than 5% of the circulating lymphocytes display the morphologic abnormalities characteristic of ATL or have an integrated HTLV-1 provirus, and patients do not have hypercalcemia, adenopathy, or hepatosplenomegaly. The CNS, bones, and GI tract are not involved, but typical skin lesions and pulmonary infiltrates may be present. The median survival for patients with the smoldering form of ATL is 5 years or longer.

Seronegative Cutaneous T Cell Lymphoma

Debate persists regarding the role of retroviruses in patients with cutaneous T cell lymphoma (CTCL) who are seronegative for HTLV-1/2. The suggestion that retroviruses are involved in the development of HTLV-1-seronegative cases of CTCL is based on disputable evidence from small studies and has not been confirmed.^66,67

Tropical Spastic Paraparesis/HTLV-1-Associated Myelopathy

TSP/HAM is a slowly progressive thoracic myelopathy that is associated with spastic paraparesis, sphincter disturbance, and variable degrees of proprioceptive and sensory dysfunction. One third of patients become bedridden within 10 years of diagnosis.⁶⁸ TSP/HAM affects women disproportionately, for reasons that are not understood.

Patients with HAM generally have high proviral levels in the blood and a stronger immune response to HTLV-1, with higher antibody titers in the CSF than in the serum. It has been proposed that the CNS involvement in HAM results from autoimmune destruction of neuronal tissue by viral-specific CD8⁺ T cells. HTLV-1 has also been associated with uveitis, arthropathy, and infective dermatitis; each of these conditions probably has an autoimmune/inflammatory pathogenesis.⁶⁹

Pathophysiologically, TSP/HAM is a progressive inflammatory process, with parenchymal infiltration of mononuclear cells into the CNS gray and white matter, resulting in severe, symmetrical white matter degeneration of the lateral columns, corticospinal tracts, and posterior columns.⁷⁰ Chronic inflammatory changes in the spinal cord, most notably a meningomyelitis of the lower thoracic cord, are a prominent feature. An inflammatory infiltrate is present on the spinal meninges, and the spinal cord parenchyma shows evidence of myelin destruction, similar to that in multiple sclerosis. In early disease, inflammatory changes are evident primarily circumferentially around venules and capillaries. Eventually, these perivascular inflammatory changes are accompanied by hyalinosis of blood vessels, meningeal fibrosis, and glial scars.

The onset of clinical manifestations in TSP/HAM is insidious. Symptoms include weakness or stiffness in one or both legs, back pain, and urinary incontinence. Peripheral neuropathy is usually mild. Physical findings include spastic paraparesis or paraplegia with hyperreflexia, ankle clonus, and extensor plantar responses (Babinski reflex). Cognitive function is usually spared, and cranial nerve involvement is distinctly unusual. The clinical presentation may resemble multiple sclerosis or the myelopathy of HIV infection. Ideally, laboratory studies in patients with suspected TSP/HAM should include magnetic resonance imaging of the brain and spinal cord, lumbar puncture, and serology. Unfortunately, most of these cases occur in resource-poor countries where MRI is not available. Diagnostic criteria have been proposed that classify TSP/HAM as definite, probable, or possible, on the basis of myelopathic symptoms, serology, or detection of HTLV-1 DNA and exclusion of other disorders.⁷¹

Demyelinating lesions are seen in the white matter and paraventricular regions of the brain and spinal cord. HTLV-1 provirus is usually not found in the cells of the CNS parenchyma, but it may be detected in a few CSF-associated lymphocytes. Although a high proviral serum level of HTLV-1 is an important risk factor for the development of HAM, the presence of provirus in the blood is not sufficient to cause disease, and the immunopathogenesis of HAM is probably associated with host genetic factors.

HTLV-1 and Autoimmune Disease

Although HTLV-1 is primarily recognized as the cause of ATL and TSP/HAM, this virus may also be involved in the development of several different autoimmune disorders, including chronic arthropathy, pulmonary alveolitis, Sjögren syndrome, uveitis, arthritis, connective tissue disease, and polymyositis. In addition, autoimmune thyroid disease has also been associated with HTLV-1 infection.

Polymyositis

An increased prevalence of polymyositis in HTLV-1 infected patients has been described.^72,73 The symptoms reported consist of fever, asthenia, severe myalgia, and muscle weakness. The laboratory test findings include abnormal serum creatine phosphokinase and serum aspartate aminotransferase levels, polyclonal hypergammaglobulinemia, the presence of circulating immune complexes, and increased levels of C3 and C4 components of complement. Myopathic changes are evident in the electromyogram. The histopathologic findings observed in muscle biopsy specimens include infiltration of lymphocytes in the endomysium and atrophic and necrotic muscles fibers with phagocytes^74,75 [see Figure 7].

Figure 7. A muscle biopsy sample from a patient with severe, steroid-responsive polymyositis who was coinfected with HIV-1 and HTLV-1 shows extensive lymphoid infiltration of muscle. HTLV-1 tax/rex messenger RNA gene products were detected in the biopsy sample.

The pathogenesis of polymyositis in HTLV-1-infected patients is currently under investigation. Autoreactive CD8⁺ T cells of HTLV-1-positive patients with polymyositis have been found to be clonally expanded⁷⁶ and can exert a myotoxic effect on muscle fibers expressing major histocompatibility complex (MHC) class I molecules.⁷⁷ Biopsy specimens from myositis patients suggest that the expression of high levels of autoantigens and MHC-I by regenerating muscle cells leads to activation of nuclear factor κβ pathways. These muscle cells may be the targets of attack by CTLs.^78,79

Uveitis

HTLV-1 can cause a specific type of intraocular inflammation characterized by acute granulomatous or nongranulomatous uveal reactions, vitreous opacities with iritis, and retinal vasculitis.^80,81 This intraocular inflammation may be mediated by cytokines produced by HTLV-1-infected CD4⁺ T cells.^82,83,84

In most patients, the uveal inflammatory and retinal vascular changes respond to topical or systemic corticosteroids and resolve in a few weeks.⁸⁵ Long-term complications of HTLV-1 uveitis include cataracts, persistent vitreous opacities, glaucoma, retinochoroidal degeneration, and optic neuropathy; the prognosis for vision may be poor.^86,87,88

Arthritis

HTLV-1 is strongly implicated in the development of a type of arthritis that resembles rheumatoid arthritis (RA) in carriers. So-called arthritogenic viruses such as HTLV-1 have been shown to generate destructive inflammatory arthritis in animal models.⁸⁹ The tax protein has been identified as a major antigen for synovial cell proliferation⁹⁰; the prevalence of HTLV-1 tax positivity in patients with RA is three times higher than in healthy blood donors.⁹¹ A therapeutic approach using tax antisense oligonucleotides has been suggested for RA patients who are HTLV-1 tax positive.⁹² Additionally, oligoclonal expansion of T cells has been found in the synovium of patients with HTLV RA. The expression of HTLV-1 env and tax mRNA was detected in the affected synovium and peripheral blood T cells of patients. The HTLV-1 env protein may also play an important antigenic role in the development of arthropathy in patients with HTLV-1-associated chronic arthritis.⁹³

Pneumonitis/lymphocyte alveolitis

Cases of lymphocytic pneumonitis have been reported in patients with TSP/HAM and autoimmune diseases (e.g., Sjögren syndrome) and in HTLV-1 carriers without associated myelopathies.^94,95 Lung biopsy specimens from HTLV-1 patients have shown marked lymphocytic infiltration, increased total cell counts, and T cell lymphocytosis in bronchoalveolar lavage fluid (BALF), providing further evidence of HTLV-1 tropism for the lung.⁹⁶ Systemic and local increase of HTLV-1 proviral DNA load may be implicated in the pathogenesis of pulmonary involvement in HTLV-1 carriers.⁹⁵ Increased levels of soluble IL-2 receptor (IL-2R), a marker of lymphocyte activation, have been reported in serum and BALF from HTLV-1 TSP/HAM patients.⁹⁷ Because T cells in the lung release soluble IL-2R, it is hypothesized that immunologic mechanisms have an important role in the development of pulmonary lesions in HTLV-1 patients.^98,99

Autoimmune thyroid disease

HTLV-1 has been associated with the development of Hashimoto thyroiditis¹⁰⁰ and Graves disease.¹⁰¹ The pathogenesis and pathobiology of HTLV-1-associated thyroid diseases has yet to be established, but production of cytokines and cellular genes by HTLV-1-infected T cells may contribute to the development of these diseases.¹⁰²

HTLV-2

Although HTLV-2 was initially regarded as a blood-borne pathogen with limited disease potential,^103,104 subsequent studies challenged that view, especially with regard to patients coinfected with HTLV-2 and HIV.^105,106 Like HTLV-1, HTLV-2 causes TSP/HAM and neurodegenerative disease but is only rarely found in patients with lymphoproliferative disease. The association of HTLV-2 with malignancy, first noted with T cell variant hairy cell leukemia,¹⁰⁷ was subsequently expanded by case reports describing the isolation of HTLV-2 from a patient with CD8⁺ T cell leukemia¹⁰⁸ and from a patient with HIV who was coinfected with CTCL.¹⁰⁹

Whether HTLV-2 has a broader role in the pathogenesis of leukemia or lymphoma remains under dispute. Careful investigations have essentially excluded a role for HTLV-2 in the pathogenesis of classic B cell hairy cell leukemia^110,111 and large cell granulocytic leukemia.¹⁰⁸

HTLV-2 is also associated with the rare development of TSP/HAM. As of 2004, there were about a dozen known cases of myelopathy associated with HTLV-2,¹¹² including four cases from a well-defined prospective cohort of 405 HTLV-2-infected blood donors (cumulative prevalence, 1.0%; 95% confidence interval, 0.3–2.5) who were followed for more than 10 years.¹¹³ Epidemiologic evidence has also linked HTLV-2 infection in these blood donors with an increased risk of infectious complications, including pneumonia, tuberculosis, and urinary tract infections.¹⁰⁴

HTLV and AIDS

HTLV-1 and HTLV-2 are frequent copathogens in HIV-1-infected individuals, especially in large metropolitan areas where injection drug use is a common mode of transmission.^114,115 Furthermore, HIV-1 and HTLV-1 coinfections have been frequently reported in geographic regions of high HTLV-1 seroprevalence, such as Brazil and the Caribbean.^116,117,118 Clinical evaluations of coinfected patients have found a frequent association with neurologic complications, including HTLV-associated myelopathy and peripheral neuropathy.^{106,119,120,121} Coinfected patients are also more likely to have hematologic complications such as thrombocytopenia, as well as respiratory, urinary tract, and hepatitis C virus infections.¹²⁰ Although highly active antiretroviral therapy (HAART) has significantly decreased AIDS-associated mortality,¹²² the potential benefit of HAART in suppressing HTLV-1/2 viral replication in HIV-infected individuals is unclear.^123,124,125 In fact, anecdotal reports suggest that HAART may actually increase HTLV-1/2 viral load.¹²⁶

A 2004 cohort study documented the clinical outcomes and survival probabilities in patients coinfected with HIV-1 and HTLV-1 or HTLV-2.¹²⁰In this study, HTLV coinfection was unexpectedly shown to result in improved survival and delayed progression to AIDS. However, an increased frequency of HTLV-associated complications was clearly evident, including TSP/HAM and peripheral neuropathy.

The dynamics of retroviral coinfections are complex. Although HIV-1, HTLV-1, and HTLV-2 all share a preferential tropism for T cells, the virologic effects of each of these three viruses differ.¹²⁷ HIV-1 is highly cytopathic for CD4⁺ T cells, whereas HTLV-1 and HTLV-2 are noncytopathic and have the potential to cause clonal proliferation and transformation of T cells.¹²⁸ Indeed, exposure to HTLV-1 or HTLV-2 can increase productive infection in HIV-1-infected cells.^129,130 However, the reciprocal effect (i.e., HIV-1 increasing HTLV-1/2) is not as well documented.¹³¹ In one patient population, levels of HTLV-1/2 tax and rex mRNA levels were higher in patients with HIV/HTLV coinfection than in those infected with HTLV-1 or HTLV-2 alone.¹³² HIV-1-induced regulatory proteins may have both autocrine and paracrine effects in HIV-1 and HTLV-1/2 coinfected microenvironments, leading to upregulated expression of HTLV-1/2.^133,134

Laboratory Diagnosis of HTLV Infection

Screening of blood donors for HTLV-1 and HTLV-2 is now routinely performed in the United States, Canada, several Caribbean countries, Europe, and Japan.¹³⁵ The primary screening assay is the EIA; the Western blot assay is used for confirmatory testing. However, EIA cannot distinguish between HTLV-1 and HTLV-2 infections because of the significant protein homology between the two viruses. Importantly, antibodies to HTLV do not cross-react with HIV proteins. After repeatedly positive results on EIA, the diagnosis of HTLV infection is confirmed if antibodies to two gene products (gag and env proteins) are detected on Western blot assay. For example, a specimen demonstrating antibody reactivity to p24gag and to pg46env or gp61/68env, or both, is considered to be positive for HTLV-1 or HTLV-2.

For specimens that test positive on EIA and that react with any of the Western blot bands but not to both gag and env, results are considered indeterminate. Specimens that test positive on EIA but that display no immunoreactivity to any of the HTLV Western blot bands are considered to be negative for antibodies to HTLV-1 and HTLV-2, and the result of the EIA is considered to be false positive. To better differentiate between HTLV-1 and HTLV-2, the Western blot assay has been modified to contain type-specific recombinant proteins from the external glycoprotein of HTVL-1 (rgp46envI) and HTLV-2 (rgp46envII), as well as a truncated recombinant peptide, rp21e, from the transmembrane glycoprotein gp21env. In one study, patients who had indeterminate Western blot assay profiles (i.e., no antibody reactivity to p24, p19, or rp21e) and who did not have risk factors for HTLV infection were shown not to be infected with either HTLV-1 or HTLV-2 by PCR amplification.¹³⁶ Such indeterminate Western blot assay results appear to represent antibodies to other viral and cellular antigens that cross-react with HTLV proteins. Nevertheless, blood donors with indeterminate results are deferred, and their blood is not used for transfusions.

PCR has become the reference method for determining infectious status, for validating serologic assays, for distinguishing between HTLV-1 and HTLV-2, for studying in vivo viral load and tissue distribution, and for further evaluation of patients with risk factors for HTLV infection whose serologic status is either indeterminate or negative.¹³⁵ PCR is also an important method of testing infants for HTLV infection, because their serologic status may be unclear, owing to the presence of passively transferred maternal antibodies. In addition, PCR is important for the detection of infection in the window period between infection and seroconversion.¹³⁵

Treatment of HTLV Disease

Adult T Cell Leukemia/Lymphoma

All patients diagnosed with ATL should be referred to a tertiary care center with expertise in the treatment of HTLV-1-associated malignancies. Conventional chemotherapy for lymphoid malignancies is ineffective against aggressive forms of ATL; therefore, treatment of ATL has become the subject of several clinical studies. Combination chemotherapy specifically designed for ATL has considerably elevated the treatment response rate in ATL patients, but it has not sufficiently extended the median survival time seen with standard cytotoxic regimens (e.g., cyclophosphamide, doxorubicin, vincristine, and prednisone), which is less than 2 years. One current trial in the United States employs oral zidovudine in combination with high doses of interferon alfa (IFN-α), administered daily.¹³⁷ Arsenic trioxide may induce cell cycle arrest and apoptosis of ATL cells in vitro, and is under consideration as an adjuvant chemotherapeutic agent in combination with IFN-α.¹³⁸ There are several reports from Japan of successful allogeneic stem cell transplantation after cytoreductive chemotherapy.^139,140Other trials have attempted immunotherapy using humanized monoclonal antibodies directed against IL-2R and other receptors expressed on ATL cells.^141,142

Additional adjuvant treatments for extranodal complications of ATL include the use of external beam irradiation for lytic bone tumors and tumors within the spinal cord, psoralen plus ultraviolet light therapy for CTCL lesions,¹⁴³ and bisphosphonates for the treatment of hypercalcemia.

Management of infectious diseases in ATL patients includes the use of trimethoprim-sulfamethoxazole prophylaxis against P. jiroveciinfection in patients with acute forms of ATL and possibly in patients with chronic ATL. Monitoring of peripheral blood for the development of cytomegalovirus (CMV) antigenemia may be advised so that ganciclovir can be started before overt CMV pneumonitis develops. ATL patients with a history of tuberculin reactivity or who have resided in countries with high rates of tuberculosis should be considered for isoniazid prophylaxis, although hepatic involvement with ATL may preclude the use of hepatotoxic drugs.

Infectious Complications

Some carriers of HTLV-1 or HTLV-2 who do not have ATL also appear to have immune deficiency, as evidenced by an increased risk of certain infectious disease complications, including strongyloidiasis.^144,145 HTLV-1-infected individuals in areas of high endemicity forStrongyloides stercoralis should probably undergo examination for stool ova and parasites, although there is no formal recommendation in this regard. There are also single case reports of other infections associated with HTLV-1/2 infection, including Norwegian scabies, disseminated molluscum contagiosum, and extrapulmonary histoplasmosis. Finally, staphylococcal and streptococcal skin infections are common in the infectious dermatitis syndrome described in Jamaica.¹⁴⁶

Autoimmune Disorders

Efforts to treat TSP/HAM and HTLV-1-associated autoimmune diseases by using various antiretroviral compounds have been disappointing.¹⁴⁷ Corticosteroids and immunosuppressive agents such as azathioprine may ameliorate disease progression but are unsuitable for long-term use because of their adverse effects.¹⁴⁸ Immunotherapy with IFN-α has produced minimal to moderate results, depending on the degree of inflammation and tissue destruction.^149,150

Vaccines

Despite the development of prototype vaccines against HTLV-1,^151,152,153 no candidate vaccine has yet advanced into clinical trials. This may be partially because of the very low seroprevalence of HTLV-1 infection in the majority of economically prosperous nations. An HTLV-2 vaccine could be beneficial in high-risk groups such as injection drug users. The greatest benefit of a vaccine might not be for protection against infection but rather as an immunomodulatory agent for the treatment of smoldering or chronic ATL.¹⁵⁴

Other Human Retroviruses

HTLV-3 and HTLV-4

The designations HTLV-3 and HTLV-4 were originally applied to HIV-1 and HIV-2, respectively; this nomenclature was changed when it was realized that HIV-1 and HIV-2 are lentiviruses, whereas HTLVs are oncornaviruses.^155,156,157 The oncornaviruses currently known as HTLV-3 and HTLV-4 were identified in central African bushmeat hunters.^3,158,159 These viruses are likely to have resulted from direct contact of hunter-gatherers with the blood of nonhuman primates, given that these viruses are very similar genetically to primate T cell lymphotropic viruses that have been isolated in a variety of nonhuman primates within rural areas of Cameroon.^159,160 Although HTLV-3 and HTLV-4 are currently limited to a small population in a remote area, population shifts resulting from deforestation and migration of rural villagers to urban areas may promote the spread of these viruses. The potential for disease with these recently discovered human retroviruses is uncertain at this time.

Human Foamy Virus

The spumaviruses, also known as foamy viruses, are characterized by their ability to induce typical cytopathic effects with syncytia formation in cultured cells.¹⁶¹ Foamy viruses possess reverse transcriptase and share genetic homology with other viruses of the familyRetroviridae.¹⁶² They appear to infect a wide variety of animals, including felines and nonhuman primates¹⁶³; nearly all species of nonhuman primates are known to be infected with simian foamy viruses.¹⁶⁴

The isolation of HFV from a nasopharyngeal carcinoma biopsy specimen was reported in 1971,¹⁶⁵ and subsequent work showed that this virus was closely related genetically to a chimpanzee foamy virus.¹⁶⁶ Serologic studies in Europe and Africa suggest a very low prevalence of seroreactivity to foamy viruses in humans.^162,167 As with HTLV-3 and HTLV-4, transmission of many HFV infections may result from close contact with body fluids and tissues of nonhuman primates.¹⁶⁸ To date, a causal link between HFV and human disease has not been identified.

Endogenous Retroviruses

Human endogenous retroviruses (HERVs) exist within the human genome, but generally they do not exist as fully organized proviruses. Portions of retroviral sequences, such as gag, pol, and env (as well as other structural and regulatory gene sequences known as retroelements) are incorporated in a complex fashion within eukaryotic DNA.¹⁶⁹ Hence, HERVs are replicated along with the host's cellular genes. Depending on the intactness of HERV retroelements, defective or fully replication-competent retroviral particles can be expressed. For example, HERV proviruses containing the gag and promoter genes, but lacking an effective pol or env, could potentially acquire the ability to assemble a viruslike particle that could not bud from the cell membrane, because it would lack an envelope. There are a few HERVs that contain nearly all viral genes, such as members of the HERV-K family.¹⁷⁰ The defective provirus, expressed in some teratocarcinoma cells, expresses several proteins, including gag, cORF, protease, polymerase, and env, and can assemble into viral particles.¹⁷¹ Members of the HERV-K family transcribe themselves under the regulation of their LTRs and express viral RNA at low levels in various human tissues and tumors.¹⁷¹ Hence, it is postulated that they may have a role in the pathogenesis of these tumors.

Expression of HERV proteins may induce autoimmunity through a variety of mechanisms.¹⁷² For example, HERV proteins might mimic host antigens or function as superantigens, resulting in activation and proliferation of T cells. Clonal expansion of T cell populations could then be expected to produce cytokines (including TNF-α, IL-1α, and IL-1β), which have been shown in some studies to upregulate HERV mRNA expression.¹⁷³

Human retroviral particles have been observed within salivary gland samples obtained from patients with Sjögren syndrome and from some HIV-seronegative patients with CD4⁺ T cell deficiency.^174,175 Seroprevalence studies have suggested that antibody reactivity to these HERVs is present in a high percentage of patients with autoimmune diseases such as systemic lupus erythematosus.¹⁷⁶ It remains unclear to what extent these viruses or their subunits actually contribute to the disease pathogenesis.¹⁷²

Acknowledgments

The authors wish to acknowledge Drs. Robert Coombs and Maureen Shuh as contributing authors.

Figure 1 Edward Murphy, M.D., University of California, San Francisco

Figure 2 Peter Didier, Ph.D, Tulane National Primate Research Center

Figure 4 Carlos Mora, M.D., Georgetown University

Figure 5 John Krause, M.D., Tulane University Health Sciences Center

Figure 6 Erin Boh, M.D., Tulane University Health Sciences Center

Figure 7 Faruk Ayden, M.D., Tulane University Health Sciences Center

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Editors: Dale, David C.; Federman, Daniel D.