Increased production of IL-7 accompanies HIV-1-mediated T-cell depletion: implications for T-cell homeostasis.

We hypothesized that HIV-1-mediated T-cell loss might induce the production of factors that are capable of stimulating lymphocyte development and expansion. Here we perform cross-sectional (n = 168) and longitudinal (n = 11) analyses showing that increased circulating levels of interleukin (IL)-7 are strongly associated with CD4+ T lymphopenia in HIV-1 disease. Using immunohistochemistry with quantitative image analysis, we demonstrate that IL-7 is produced by dendritic-like cells within peripheral lymphoid tissues and that IL-7 production by these cells is greatly increased in lymphocyte-depleted tissues. We propose that IL-7 production increases as part of a homeostatic response to T-cell depletion.

Human herpesvirus 6 (HHV-6) causes severe thymocyte depletion in SCID-hu Thy/Liv mice.

Human herpesvirus 6 (HHV-6) is a potentially immunosuppressive agent that may act as a cofactor in the progression of AIDS. Here, we describe the first small animal model of HHV-6 infection. HHV-6 subgroup A, strain GS, efficiently infected the human thymic tissue implanted in SCID-hu Thy/Liv mice, leading to the destruction of the graft. Viral DNA was detected in Thy/Liv implants by quantitative polymerase chain reaction (PCR) as early as 4 d after inoculation and peaked at day 14. The productive nature of the infection was confirmed by electron microscopy and immunohistochemical staining. Atypical thymocytes with prominent nuclear inclusions were detected by histopathology. HHV-6 replication was associated with severe, progressive thymocyte depletion involving all major cellular subsets. However, intrathymic T progenitor cells (ITTPs) appeared to be more severely depleted than the other subpopulations, and a preferred tropism of HHV-6 for ITTPs was demonstrated by quantitative PCR on purified thymocyte subsets. These findings suggest that thymocyte depletion by HHV-6 may be due to infection and destruction of these immature T cell precursors. Similar results were obtained with strain PL-1, a primary isolate belonging to subgroup B. The severity of the lesions observed in this animal model underscores the possibility that HHV-6 may indeed be immunosuppressive in humans.

An AIDS-like condition induced in baboons by HIV-2.

Six baboons (Papio cynocephalus) were intravenously inoculated with the human immunodeficiency virus-type 2 (HIV-2) strain HIV-2UC2. All seroconverted within 6 weeks after inoculation; five animals became persistently infected. Four developed lymphadenopathy, and three of the animals had CD4+ T cell loss within 18 to 24 months after inoculation. One of these baboons, showing severe clinical symptoms, showed at necropsy widespread dissemination of virus with follicular depletion in the lymph nodes, extensive fibromatosis involving lymphoid and nonlymphoid tissues, and lymphocytic interstitial pneumonitis. Another animal is cachectic and exhibited lymphoid follicular lysis and fibrous skin lesions. Other baboons inoculated with a second strain, HIV-2UC14, have shown evidence of persistent infection. HIV-2 infection of baboons provides a valuable animal model for studying HIV persistence and pathogenesis and for evaluating approaches to antiviral therapies.

Human immunodeficiency virus-infected macrophages produce soluble factors that cause histological and neurochemical alterations in cultured human brains.

We wanted to establish an in vitro human model for AIDS-associated dementia and pursue the hypothesis that this disease process may be a result of soluble factors produced by HIV-infected macrophages. Human brain aggregates were prepared from nine different brain specimens, and were treated with supernatants from in vitro HIV-infected macrophages (SI), uninfected macrophages (SU), infected T cells, or macrophage-conditioned media from four AIDS patients. Seven of nine treated brains exposed to SI showed peripheral rarefaction after 1 wk of incubation that by ultrastructural analysis showed cytoplasmic vacuolation. Aggregates from two of three brain cultures treated with SI for 3 wk became smaller, an approximately 50% decrease in size. The degree of apparent toxicity in brains exposed to patient-derived macrophage supernatants paralleled the proportion of macrophages found to be expressing HIV p24. Ultrastructural abnormalities were not observed in brains treated with supernatants from HIV-infected T cells, uninfected macrophages, or LPS-activated macrophages. Levels of five neurotransmitter amino acids were decreased in comparison to the structural amino acid leucine. These findings suggest that HIV-infected macrophages, infected both in vitro as well as derived from AIDS patients' peripheral blood, produce factors that cause reproducible histochemical, ultrastructural, and functional abnormalities in human brain aggregates.

Identification of a common clonal human immunodeficiency virus integration site in human immunodeficiency virus-associated lymphomas.

Infection with human immunodeficiency virus type 1 (HIV-1) is associated with a high incidence of lymphoma. Typically, the lymphomas are B-cell in origin, and although they occur in the setting of HIV-1 infection, historical studies have found no evidence for the presence of HIV-1 within the transformed B-cells. We describe a new class of large cell lymphoma wherein HIV p24 expression within the tumor specimens was found to be extremely high. In the first case, HIV was expressed in the tumor-associated transformed T-cells. In three other cases, HIV was found to be highly expressed in tumor-associated macrophages. These tumors exhibited a mixed immunophenotype histologically. Analysis by inverse polymerase chain reaction, using HIV long terminal repeat primers, demonstrated monoclonal HIV integration sites for all four tumors. Direct sequencing of the T-cell lymphoma inverse polymerase chain reaction products identified the HIV integration site within the fur gene, just upstream from the c-fes/fps protooncogene. Using segments of the fur gene as a probe, the other three monoclonal integration sites mapped to the same region. Although the integration and up-regulation of c-fes/fps was localized to the tumor cells within the T-cell lymphoma, the cells containing the monoclonal HIV in the other mixed immunophenotype lymphomas are currently unknown. These observations suggest that HIV may contribute directly to lymphomagenesis and identify a common site of HIV integration within a subset of acquired immunodeficiency syndrome lymphoma.

Purified trichosanthin (GLQ223) exacerbation of indirect HIV-associated neurotoxicity in vitro.

A formulated preparation of trichosanthin (GLQ223, Pharmaceutical Development Group, Genelabs Inc., Redwood City, California, USA) has been shown to selectively inhibit HIV replication in vitro in lymphocytes and macrophages. In view of recent anecdotal reports of central nervous system (CNS) complications associated with trichosanthin use in some HIV-infected patients, we evaluated any potential drug effects leading to neurotoxicity using a human brain cell aggregate model. Brain cell aggregate cultures were incubated with dilutions of purified trichosanthin alone (trichosanthin), supernatants of HIV-infected macrophage cultures (S-HIV), supernatants of uninfected macrophage cultures (S-U), supernatants of purified trichosanthin-treated uninfected macrophage cultures (S-trichosanthin), or supernatants of purified trichosanthin-treated HIV-infected macrophage cultures (S-HIV-trichosanthin). Treatment with purified trichosanthin alone at up to 2 micrograms/ml, with S-U or with S-trichosanthin, produced no morphological signs of toxicity to brain cell aggregate cultures. S-trichosanthin treatment at 2 micrograms/ml did not result in a significant change in cyclic nucleoside phosphorylase (CNP) activity. Treatment of the brain aggregates with S-HIV and S-HIV-trichosanthin did, however, result in morphological alteration of the brain aggregates, with S-HIV-trichosanthin-treated brain aggregates showing the most severe damage. Although purified trichosanthin did not appear to be directly toxic to human brain aggregate cultures, trichosanthin treatment of infected macrophages may have increased the morphological alterations caused by supernatants of HIV-infected macrophages. These experimental observations may explain anecdotal reports of adverse CNS reactions in association with trichosanthin treatment of HIV-infected patients and emphasize the neurotoxic potential of any therapy targeted at HIV-infected macrophages.

Pathogenesis of AIDS lymphomas.

The AIDS-associated lymphomas represent a heterogeneous set of disease processes. The largest histologic subset of lymphomas is the large-cell lymphomas, which represent a spectrum of disease processes ranging from monomorphic monoclonal B-cell proliferations to very polymorphic and polyclonal mixtures of B cells, T cells and macrophages. The next most frequent class of systemic lymphoma are the small non-cleaved cell or Burkitt's-like lymphomas. These are relatively monomorphic, monoclonal malignant B-cell proliferations. The final subset of lymphomas, which are likely to become more common as the AIDS epidemic progresses, are the primary CNS lymphomas, which are expansions of EBV-immortalized B cells. The high incidence of tumor-associated EBV in the CNS lymphomas makes these lesions somewhat analogous to an opportunistic EBV infection. In HIV disease there is a long lag after infection before the appearance of clinical manifestations of impaired T-cell immunity. During this period, both appropriate B-cell proliferation in response to antigen (including the ubiquitous HIV) and abnormal B-cell proliferation (autoimmune, dysregulated) occur as the follicular architecture is disrupted by the virus and potential APC are exposed and/or infected with HIV. The destruction of FDC or the involution of their processes could interfere with the elimination by apoptosis of low-avidity B-cell clones. Antigen-competent B cells with pre-existing chromosomal translocations such as the t(8;14) (c-myc, IgH) would have a selective growth advantage in this setting. Figure 9 shows a schematic representation of prelymphomatous and lymphomagenic events as they are projected to occur. A similar pathogenetic scheme has been postulated for follicular B-cell lymphomas: PCR studies have demonstrated that a pool of t(14;18) (IgH;bcl-2) B-cells are present in lymph nodes featuring follicular hyperplasia. In response to antigen (the evidence favoring antigen drive is extensive hypersomatic mutation in sequences related to binding sites), B cells with the t(14;18) translocation have a selective advantage because the bcl-2 oncogene confers a resistance to apoptosis. Burkitt's lymphomas, particularly sporadic or HIV variants, fulfill at least the key criteria for antigen competence, mainly the presence of surface Ig. The c-myc-associated chromosomal translocational events are likely to occur early during the enzymatic machinations of gene rearrangement. Such B cells would be in the dysregulated cytokine and antigen milieu of HIV disease and ultimately could have a selective advantage. EBV infection of B cells probably requires activation and expression of the CD21 receptor. Furthermore, CD5+ B cells of CLL are refractory to EBV infection.(ABSTRACT TRUNCATED AT 400 WORDS)

Characterization of a human Kaposi's sarcoma cell line that induces angiogenic tumors in animals.

OBJECTIVE: To characterize a Kaposi's sarcoma (KS) cell line established from a tumor biopsy from the oral mucosa of an iatrogenically immunosuppressed HIV-negative man. METHODS: Cells were placed in culture and evaluated by a variety of biologic, serologic, karyotypic, and immunologic procedures. Electron microscopic examination was performed. The ability to produce tumors in nude mice was evaluated, and the nature of the cells within the tumor determined. Assays for urokinase plasminogen activator type (uPA), plasminogen activator inhibitor-1 (PAI-1) and the urokinase receptor (uPAR) were conducted. RESULTS: The SLK cell line has an endothelial cell morphology with very little anaplasia. The karyotype indicates diploid phenotype of human origin. Immunohistochemical and electron microscopic examinations confirmed the endothelial nature of this cell line. No viruses were detected. The tumors induced in nude mice showed hypervascularization, with characteristics of KS. The cell line produces uPA and PAI-1, and also expresses uPAR. CONCLUSIONS: The SLK cell line is of endothelial cell origin and the first human cell line to induce KS-like tumors in recipient animals. The expression of urokinase and its receptor suggests a paracrine and autocrine interaction that may be important for the growth of the tumor. The SLK line should be valuable for studies of KS pathogenesis and therapeutic approaches to this malignancy.

No evidence of human herpesvirus 8 infection in patients with paraneoplastic pemphigus, pemphigus vulgaris, or pemphigus foliaceus.

Paraneoplastic pemphigus has been associated with both malignancies and multicentric Castleman's disease; the latter is a rare angiolymphoproliferative disorder that has also been linked with human herpesvirus 8 (HHV8) infection. Other diseases definitively associated with HHV8 include Kaposi's sarcoma and primary effusion lymphoma. In a search for additional HHV8-associated diseases, patients with paraneoplastic pemphigus, as well as patients with pemphigus vulgaris and pemphigus foliaceus, were studied. Using an immunofluorescence assay able to specifically detect antibodies directed against lytically induced HHV8 antigens, HHV8 antibodies were not detected in sera from 24 patients with paraneoplastic pemphigus (including 10 with concomitant Castleman's disease) nor from 19 patients with pemphigus vulgaris. Sera from patients with Kaposi's sarcoma and from healthy U.S. blood donors were positive (25 of 26) and negative (none of 20), respectively. In addition, HHV8 DNA was not found in frozen lesional skin of five patients with pemphigus vulgaris and five patients with pemphigus foliaceus by nested polymerase chain reaction (lower limit of detection = 10 copies viral DNA per microg total cellular DNA). Finally, tissue sections of lesional skin from 10 patients with pemphigus vulgaris were negative for HHV8 by in situ hybridization, using probes able to detect both latently and lytically expressed HHV8 genes in Kaposi's sarcoma tissue. In summary, no evidence of HHV8 infection was found in all types of pemphigus using a variety of methods. These findings do not support a general role for HHV8 in skin diseases associated with immunosuppression.

The usefulness of diagnostic bone marrow examination in patients with human immunodeficiency virus (HIV) infection.

To determine the utility of bone marrow examination for the diagnosis of opportunistic infections and lymphoma in patients with known or suspected human immunodeficiency virus (HIV) infection, we retrospectively reviewed the medical and laboratory records of all patients undergoing diagnostic bone marrow examinations at San Francisco General Hospital between January 1, 1988 and December 31, 1989. All marrow examinations of patients with known or suspected HIV infection in which specimens were examined histopathologically and/or microbiologically for opportunistic pathogens or lymphoma were analyzed. Bone marrow examination resulted in the diagnosis of mycobacterial infection in 16% of the patients studied. Blood culture was 77% sensitive and bone marrow culture was 86% sensitive for detecting disseminated mycobacterial infection. This difference was not statistically significant (p greater than 0.05). Disseminated fungal infections occurred in less than 5% of the patients studied, and most were rapidly and accurately detected by examination of stained bone marrow samples. No case of lymphoma was diagnosed by bone marrow examination. Bone marrow examination may be useful for diagnosing opportunistic infections in patients with HIV infection. Mycobacterial blood cultures have a sensitivity comparable to bone marrow cultures in detecting disseminated mycobacterial infections, are less invasive, and may be less costly. Marrow examination is not useful for diagnosing lymphoma but can determine the extent of lymphoma that has been diagnosed by other means.

The diagnostic utility of the keratin profiles of hepatocellular carcinoma and cholangiocarcinoma.

A total of 32 hepatocellular carcinomas (HCC), 10 cholangiocarcinomas (CC), one combined HCC-CC, and 10 adenocarcinomas metastatic to the liver were studied immunohistochemically using AE1 and Cam 5.2, monoclonal antikeratin antibodies with different specificities. AE1 recognizes keratins with molecular weights of 56.5, 50/50', 48, and 40 kd (keratin nos. 10, 14, 15, 16, and 19, according to Moll's catalog), and labels many epithelia, including bile duct epithelium, but not hepatocytes. Both biliary epithelium and hepatocytes are stained by Cam 5.2, which reacts with keratins of molecular weights 50, 43, and 39 kd (corresponding to keratin nos. 8, 18, and 19). Tissues were formalin fixed, paraffin embedded, and a three-stage immunoperoxidase technique was employed. Of 32 pure HCCs, 29 were unreactive with AE1 yet were positive with Cam 5.2. The intensity and extent of immunostaining with Cam 5.2 did not correlate with tumor grade. In contrast to the HCCs, all 10 CCs and the 10 hepatic metastases were strongly positive with both AE1 and Cam 5.2. The combined HCC-CC was also labeled by both antibodies. We conclude that most HCCs express an immunohistochemical keratin profile identical to that of nonneoplastic hepatocytes, which differs from the keratin patterns of bile ducts, CCs, and metastatic adenocarcinomas from a variety of primary sites. These differences in immunoreactivity with antikeratin antibodies may prove useful in diagnostic surgical pathology.

VH gene use by HIV type 1-associated lymphoproliferations.

The pathogenesis of polyclonal HIV-associated lymphomas lacking traditional B cell cofactors (i.e., Epstein-Barr virus [EBV] infection, c-myc translocations) is poorly understood. A multistep pathogenesis model has been proposed in which polyclonal lymphomas represent an earlier stage in HIV-associated lymphomagenesis before the emergence of a dominant malignant clone. Chronically present antigens have been proposed as a likely stimulus for polyclonal B cell proliferation; if so, polyclonal lymphoma-associated immunoglobulins (Igs) should have molecular evidence of somatic hypermutation, a process by which antibody affinity maturation in response to chronic antigenic stimulation occurs. Molecular analyses of Ig heavy chain variable (V(H)) gene use by B cells in a polyclonal HIV-associated large cell lymphoma lacking EBV and c-myc rearrangement was undertaken. Eighteen randomly selected clones generated from RT-PCR yielded 15 unique V(H) sequences, all of which were most homologous to only three previously identified germline V(H)1 genes. Two sets of clones (consisting of three and two clones, respectively) had identical V(H) gene sequences, and one pair of clones had identical third complementarity determining regions (CDR3s) but different V(H) gene sequences; eight clones were <95% homologous to their most related germline V(H)1 genes. We compared these results with Ig V(H)1 gene use by B cells present in a reactive hyperplastic lymph node obtained from an HIV-1-infected individual. Fifteen clones randomly selected from RT-PCRs yielded 15 unique V(H)1 sequences, all of which were most homologous to 5 previously identified germline V(H)1 genes; 10 clones were <95% homologous to their most related germline gene. Binomial probability analysis revealed that only 1 of the 15 unique V(H)1 sequences derived from the polyclonal lymphoma (i.e., 7%), as compared with 5 of 15 unique V(H)1 sequences derived from the reactive lymph node (i.e., 33%), had a low probability of occurrence by random chance (p < 0.05). These data provide molecular evidence of polyclonality in an HIV-associated polyclonal lymphoma, demonstrate a qualitative difference in somatic hypermutations of Ig V(H) genes associated with malignant versus reactive B cell lymphoproliferations, and support an antigen-mediated multistep pathogenesis model of HIV-1-associated lymphomagenesis.

Transient virus infection and pathogenesis of a new HIV type 2 isolate, UC12, in baboons.

We have previously shown that baboons (Papio cynocephalus) can be persistently infected with HIV-2 and some baboons progress to an AIDS-like disease with a CD4+ T cell decline, cachexia, alopecia, and Kaposi's sarcoma-like fibromatosis. In this study, we found that a new virus isolate, HIV-2UC12, replicated to high levels in baboon peripheral blood mononuclear cells (PBMCs) in vitro. Three baboons were subsequently inoculated and had plasma viral RNA loads that peaked between 15,000 and 7000 copies/ml at 2 weeks postinfection. Virus was isolated from the PBMCs for up to 6 months. Although PBMCs were subsequently virus culture negative, virus could be recovered from the spleen, lymph nodes, and tonsils, indicating that HIV-2 was sequestered within these lymphoid tissues. HIV-2-associated pathology included follicular lysis, vascular proliferation, and lymphoid depletion. This study indicated that HIV-2UC12 infection in baboons can cause HIV-associated pathological abnormalities within the lymphatic tissues and that the high level of HIV-2UC12 replication in vitro was not predictive of replication in vivo.

Immunohistochemical staining in malignant mesotheliomas.

The immunoreactivity of five antibodies was evaluated on six routinely processed mesotheliomas to evaluate their ability to distinguish mesothelioma from metastatic adenocarcinoma. The diagnosis in all cases was confirmed by electron microscopic examination and histochemical stains for neutral mucin (periodic acid-Schiff-diastase) and acid mucin (alcian blue with and without hyaluronidase). AE1, a monoclonal antikeratin antibody that stains most carcinomas, reacted with all six cases of mesothelioma. HMFG-2 and anti-epithelial membrane antigen (antibodies reactive with human milk fat globule proteins), two other closely related antibodies reactive with most carcinomas, also reacted with all of the mesotheliomas in the authors' series. A polyclonal antibody to carcinoembryonic antigen (anti-CEA) did not stain any of the mesotheliomas in their series. Anti-Leu-M1 did not react with the mesotheliomas. The authors conclude that none of these antibodies, when used alone on routinely fixed paraffin-embedded material, is both sensitive and specific in the distinction of mesothelioma from adenocarcinoma. However, immunoperoxidase studies using anti-CEA and anti-Leu-M1 may occasionally be helpful when used in conjunction with other histochemical stains and electron microscopic examination in distinguishing mesothelioma from metastatic adenocarcinoma.

Cutaneous presentations of lymphoma in human immunodeficiency virus disease. Predominance of T cell lineage.

BACKGROUND AND DESIGN: Most non-Hodgkin's lymphomas in patients with human immunodeficiency virus infection are of B-cell lineage. Cutaneous lymphoma in the human immunodeficiency virus disease has not been systematically reviewed. We studied 25 patients with both human immunodeficiency virus infection and cutaneous presentations of lymphoma, using immunohistochemistry and in situ hybridization for Epstein-Barr virus. RESULTS: Two groups of patients were discerned: (1) those with conditions similar to mycosis fungoides or Sézary syndrome with an indolent course (n = 8) and (2) those with nodules or papules, greater immunosuppression, a rapid clinical course, and large cell lymphoma seen on biopsy specimens (n = 17). The epidermotropic lymphomas were T-cell lineage and CD30-. Thirteen of the large cell lymphomas were also of the T-cell type, and 71% were CD30+. Epstein-Barr virus was absent in the epidermotropic lymphomas, but it was present in 73% of the nonepidermotropic cases. CONCLUSIONS: Two forms of human immunodeficiency virus-associated cutaneous lymphoma were found: indolent disease resembling mycosis fungoides or Sézary syndrome and large cell lymphomas with a poor prognosis, whose cells often had a CD30+ T-cell phenotype and harbored the Epstein-Barr virus.

A case of composite Hodgkin's disease and chronic lymphocytic leukemia in bone marrow. Lack of Epstein-Barr virus.

We report Hodgkin's disease arising in a 68-year-old patient with a history of chronic lymphocytic leukemia for 8 years. The patient presented with a 4-month history of weakness, loss of appetite, and a 15-pound weight loss. A bone marrow biopsy showed two distinct histologic types of lymphoma: chronic lymphocytic leukemia and Hodgkin's disease. Immunohistochemical studies showed that chronic lymphocytic leukemia cells were composed of kappa-light chain-restricted monoclonal B cells. The Reed-Sternberg cells expressed CD15. Epstein-Barr virus RNA was not identified in either the Reed-Sternberg cells or cells of chronic lymphocytic leukemia by in situ hybridization. To our knowledge, this is the second reported case of composite Hodgkin's disease and chronic lymphocytic leukemia involving the bone marrow.

Comparative genomic analyses of primary effusion lymphoma.

BACKGROUND: A rare subset of human immunodeficiency virus (HIV) lymphomas, known as primary effusion lymphomas (PELs), are high-grade tumors carrying human herpes virus 8. Mechanisms postulated to contribute to lymphomagenesis include impaired immune surveillance, alterations in hemopoietic regulatory pathways due to expressed viral genes, and acquisition of genomic alterations in regions of the genome that contain regulatory genes. In PEL, limited information exists about the nature of genome-wide aberrations in these rare lymphomas. METHODS: We used comparative genomic hybridization to detect regions of sequence gain and loss throughout the genome of 8 PEL cases. Regions of DNA sequence loss or gain were confirmed using forward and reverse hybridization and t-statistic analyses. RESULTS: Genomic aberrations were identified in 6 of 8 cases, including recurrent gain of sequence in chromosomes 12 [ish enh (12q22;12q23, 12q12;12q23)] in 3 of 8 cases and X [ish enh (X, Xp)] in 2 of 8 cases. CONCLUSIONS: DNA copy number changes occurred in a majority of PEL cases and are consistent with changes observed in other HIV lymphomas. These observations suggest that common genetic events may occur in HIV-associated lymphoid malignancies, but they probably do not contribute to the unique markers and morphology of PEL. Although individual genetic loci have been evaluated previously in a few PEL cases, to our knowledge this study represents the first reported genome-wide scan of copy number changes in these rare HIV-associated tumors.

Human immunodeficiency virus-2 infection in baboons is an animal model for human immunodeficiency virus pathogenesis in humans.

OBJECTIVE: To assess disease progression in baboons (Papio cynocephalus) that were infected with two human immunodeficiency virus-2 (HIV-2) isolates. METHODS: Eight baboons were inoculated intravenously with either HIV-2UC2 or HIV-2UC14 and were followed for a 2- to 7-year period of observation. RESULTS: Six of 8 baboons showed lymphadenopathy and other signs of HIV-related disease, 3 of 8 baboons had an acute phase CD4+ T-cell decline, and 2 of 5 baboons infected with the HIV-2UC2 isolate progressed to an acquired immunodeficiency syndrome-like disease. Human immunodeficiency virus-2-specific pathology in lymphatic tissues included follicular lysis, vascular proliferation, and lymphoid depletion. Both neutralizing antibodies and a CD8+ T-cell antiviral response were associated with resistance to disease. CONCLUSIONS: Disease progression and the development of acquired immunodeficiency syndrome in HIV-2-infected baboons have similarities to human HIV infections.