Immunization of simian immunodeficiency virus-infected rhesus monkeys with soluble human CD4 elicits an antiviral response.

Since the CD4 molecule is a high-affinity cell-surface receptor for the human immunodeficiency virus (HIV), it has been suggested that a soluble truncated form of CD4 may compete with cell-surface CD4 for HIV binding and thus be of use in the therapy of AIDS. We have utilized the simian immunodeficiency virus of macaques (SIVmac)-infected rhesus monkeys to explore another possible therapeutic application of CD4 in AIDS--the use of recombinant soluble CD4 (rsCD4) as an immunogen. SIVmac-infected rhesus monkeys immunized with human rsCD4 developed not only an anti-human CD4 but also an anti-rhesus monkey CD4 antibody response. Coincident with the generation of this antibody response, SIVmac could not be isolated easily from peripheral blood lymphocytes and bone marrow macrophages of these animals. Furthermore, the decreased number of both granulocyte/macrophage and erythrocyte colonies grown from the bone marrow of these immunized monkeys rose to normal levels. These findings suggest that a modified human CD4 molecule serving as an immunogen might elicit an antibody response in man that could induce a beneficial therapeutic response in HIV-infected individuals.     

Detection of viral RNA in CD4(-)CD8(-) and CD4(-)CD8(+) lymphocytes in vivo in rhesus monkeys infected with simian immunodeficiency virus of macaques

A definition of the specific cell types that support HIV replication early in the course of infection will be important for understanding AIDS pathogenesis and designing strategies for preventing infection. Observations have indicated that the population of lymphocytes susceptible to productive infection extends beyond activated CD4(+) T cells. To explore this issue, we have employed laser scanning cytometry technology and the techniques of lymphocyte surface immunophenotyping followed by fluorescent in situ hybridization to detect simian immunodeficiency virus of macaques (SIVmac) RNA in phenotypically defined rhesus monkey lymphocytes. The immunophenotype of productively infected cells in either a rhesus monkey T cell line or in PBMCs infected in vitro with SIVmac was remarkably similar to that observed in productively infected PBMCs obtained from monkeys during primary infection. We observed low levels or no detectable expression of CD4 on cells infected in vitro or on PBMCs of infected monkeys. However, a substantial number of SIVmac-infected PBMCs both in cultured lymphocytes and sampled directly from infected monkeys expressed CD8 but not CD4. These observations are consistent with the possibility that the CD4 molecule may be modulated off the surface of CD4(+)CD8(-) or CD4(+)CD8(+) lymphocytes after infection or that infection occurred via a CD4-independent mechanism. Moreover, there was no preferential expression of CD25 on cells positive for SIVmac RNA, which might have been predicted if replication of the virus was occurring selectively in activated lymphocytes. These results broaden the range of lymphocytes that support productive SIVmac infection to include CD4(-)CD8(-) and CD4(-)CD8(+) subsets, and are consistent with virus replication occurring in nonactivated cells.     

Simian immunodeficiency virus-specific cytotoxic T lymphocytes and cell-associated viral RNA levels in distinct lymphoid compartments of SIVmac-infected rhesus monkeys

Major histocompatibility class I-peptide tetramer technology and simian immunodeficiency virus of macaques (SIVmac)-infected rhesus monkeys were used to clarify the distribution of acquired immunodeficiency syndrome virus-specific cytotoxic T lymphocytes (CTL) in secondary lymphoid organs and to assess the relationship between these CTL and the extent of viral replication in the various anatomic compartments. SIVmac Gag epitope-specific CD8(+) T cells were evaluated in the spleen, bone marrow, tonsils, thymus, and 5 different lymph node compartments of 4 SIVmac-infected rhesus monkeys. The average percentage of CD8(+) T lymphocytes that bound this tetramer in all the different lymph node compartments was similar to that in peripheral blood lymphocytes in individual monkeys. The percentage of CD8(+) T cells that bound the tetramer in the thymus was uniformly low in the monkeys. However, the percentage of CD8(+) T cells that bound the tetramer in bone marrow and spleen was consistently higher than that seen in lymph nodes and peripheral blood. The phenotypic profile of the tetramer-binding CD8(+) T lymphocytes in the different lymphoid compartments was similar, showing a high expression of activation-associated adhesion molecules and a low level expression of naive T-cell-associated molecules. Surprisingly, no correlation was evident between the percentage of tetramer-binding CD8(+) T lymphocytes and the magnitude of the cell-associated SIV RNA level in each lymphoid compartment of individual monkeys. These studies suggest that a dynamic process of trafficking may obscure the tendency of CTL to localize in particular regional lymph nodes or that some lymphoid organs may provide milieus that are particularly conducive to CTL expansion. (Blood. 2000;96:1474-1479)     

Flow cytometric detection of receptors for interleukin-6 on bone marrow and peripheral blood cells of humans and rhesus monkeys

The expression of receptors for interleukin-6 (IL-6) on human and rhesus monkey peripheral blood and bone marrow (BM) cells was examined by multiparameter flow cytometry after staining with biologically active, biotin-labeled human IL-6 and phycoerythrin-conjugated streptavidin. Consistent with the multiple biologic effects of IL-6 in stimulating immune functions and hematopoiesis, IL-6 receptors were detectable on a wide variety of cell types. In peripheral blood, IL-6 receptors were detectable on monocytes, granulocytes, and on CD4+ T lymphocytes but not on resting, CD19+ B lymphocytes and CD56+ natural killer (NK) cells. CD8+ T lymphocytes also expressed IL-6 receptors but at lower levels than CD4+ cells. The IL-6 receptors on granulocytes were only detectable after staining with high concentrations of biotin- IL-6, suggesting that most IL-6 receptors on these cells represent low- affinity sites. In contrast, IL-6 receptors on both CD4+ and CD8+ T lymphocytes were detectable at biotin-IL-6 concentrations as low as 10 pmol/L, indicating that these cells bind IL-6 with high affinity. IL-6 receptor expression patterns on rhesus monkey and human blood cells were very similar except that receptor levels on granulocytes were lower in humans than in rhesus monkeys. Similar differences in expression levels were observed for IL-6 receptors that were detectable on most granulocyte precursors in the mononuclear fraction of rhesus monkey and human bone marrow. In addition to these relatively mature cell types, IL-6 receptors were detectable on a large fraction of human and rhesus monkey BM blast cells that express the CD34 antigen. The presence of IL-6 receptors on CD34+ BM blast cells, which are the precursor cells of most, if not all, BM-derived blood cells, is consistent with the ability of IL-6, in conjunction with other cytokines, to stimulate immature hemopoietic cells in vitro and to promote blood cell production when administered in vivo.     

Simian immunodeficiency virus (SIV)-specific cytotoxic T lymphocytes in gastrointestinal tissues of chronically SIV-infected rhesus monkeys.

Although systemic virus-specific cytotoxic T lymphocyte (CTL) responses are of critical importance in controlling virus replication in individuals infected with human immunodeficiency virus 1 (HIV-1), little is known about this immune response in the gastrointestinal (GI) tract. This study investigated the GI tract CTL response in a nonhuman primate model for HIV-1 infection, simian immunodeficiency virus (SIV)-infected rhesus monkeys. Lymphocytes from duodenal pinch biopsy specimens were obtained from 9 chronically SIVmac-infected rhesus monkeys and GI tract lymphocytes were harvested from the jejunum and ileum of 4 euthanized SIVmac-infected rhesus monkeys. Lymphocytes were also assessed in GI mucosal tissues by in situ staining in histologic specimens. SIVmac Gag-specific CTLs were assessed in the monkeys using the tetramer technology. These GI mucosal tissues of chronically SIVmac-infected rhesus monkeys contained levels of CTLs comparable to those found in the peripheral blood and lymph nodes. The present studies suggest that the CD8(+) CTL response in GI mucosal sites is comparable to that seen systemically in SIVmac-infected rhesus monkeys.     

CD8+ T lymphocytes of African green monkeys secrete an immunodeficiency virus-suppressing lymphokine.

Following natural and experimental infection by simian immunodeficiency virus SIVagm of African green monkeys (AGMs), the natural host, there is no evidence for the development of an immunodeficiency. Within the framework of our studies on human immunodeficiency virus (HIV)/SIV pathogenesis, we investigated the influence of CD8 T lymphocytes on SIVagm replication in AGM CD4 T lymphocytes in vitro. The following observations were made: (i) Peripheral blood mononuclear cells from both seronegative and seropositive AGMs contained only a low proportion (i.e., 10%) of CD4+ lymphocytes, whereas a high proportion (80%) of CD8+ cells was detected. Even after persistent SIVagm infection, CD4 T lymphocytes do not decrease in number. (ii) The target of in vitro infection of peripheral blood cells is the CD4+ mononuclear cell (T lymphocytes, monocytes) and SIVagm infects by binding to the CD4 molecule. (iii) In both naturally and experimentally SIVagm-infected AGMs the CD4+ T cells and monocytes, but not the CD8+ T cells, harbor DNA provirus. (iv) Virus reisolation and virus replication of SIVagm in CD4 T lymphocytes from seropositive AGMs is suppressed in the presence of autologous CD8 T lymphocytes or a soluble factor produced by these cells. Taken together, one possible reason for the apathogenicity of the SIVagm infection in AGMs may be the suppression of virus replication by a soluble, yet unidentified factor secreted by CD8 lymphocytes quantitatively dominating among peripheral blood cell populations. We have tentatively termed this factor "immunodeficiency virus-suppressing lymphokine." In addition, we show that immunodeficiency virus-suppressing lymphokine from AGMs is able to suppress HIV-1 replication in human CD4+ T cells.     

Effect of complement consumption by cobra venom factor on the the course of primary infection with simian immunodeficiency virus in rhesus monkeys

Cobra venom factor (CVF)-induced consumption of complement proteins was used to investigate the role of complement in vivo in the immunopathogenesis of simian immunodeficiency virus of macaques (SIVmac) infection in rhesus monkeys. Repeated administration of CVF was shown to deplete complement to <5% of baseline hemolytic activity of serum complement for 10 days in a normal monkey. Three groups of SIVmac-infected animals were then evaluated: monkeys treated with CVF resulting in complement depletion from days -1 to 10 postinfection, monkeys treated with CVF resulting in complement depletion from days 10 to 21 postinfection, and control monkeys that received no CVF. CD8+ SIVmac-specific cytotoxic T lymphocyte (CTL) generation and CD4+ T lymphocyte depletion during primary infection were not affected by CVF treatment. Viral load, assessed by measurements of plasma p27gag antigen and viral RNA, was transiently higher during the first 4 weeks following infection in the CVF-treated monkeys and the subsequent clinical course in these treated animals was accelerated. These results suggest that complement proteins may participate in immune defense mechanisms that decrease virus replication following the initial burst of intense viremia during primary SIVmac infection. However, we cannot rule out that the observed increased virus replication was induced by immune activation resulting from the administration of a foreign antigen to these monkeys.     

SIV/HIV recombinants and their use in studying biological properties.

A series of chimeric clones between human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency viruses (SIV) were constructed. Viability of the recombinant viruses was dependent on the position of recombination. Infectious chimeric viruses between HIV-1 and SIVAGM (isolated from an African green monkey) and those between HIV-1 and SIVMAC (isolated from a rhesus monkey) were examined for host cell tropism. Viral determinants that restrict the replication of SIVAGM in human MT-4 cells and that of HIV-1 in macaque monkey peripheral blood mononuclear cells (PBMC) mapped to the 5' half of the virus genome. One HIV-1/SIVMAC chimera which contained the HIV-1 env gene was shown to replicate in macaque PBMC in vitro and to infect macaque monkeys in vivo. This HIV-1/SIVMAC chimera will be useful for a variety of AIDS pathogenesis and vaccine studies.     

A humanized,nondepleting anti-CD4 antibody that blocks virus entry inhibits virus replication in rhesus monkeys chronically infected with simian immunodeficiency virus

Therapeutic approaches that interfere with viral entry hold promise in preventing or treating HIV infection. Hu5A8, a humanized monoclonal antibody against CD4, was previously shown to inhibit HIV and SIV replication in vitro and was safely administered to rhesus monkeys without depleting CD4(+) T cells. This antibody completely suppressed replication of six different SIVmac 251 primary isolates in vitro. Twice weekly administration of 3-mg/kg doses of hu5A8 for 2 to 4 weeks to SIV-infected rhesus monkeys resulted in sustained plasma antibody levels of > or =20 microg/ml during treatment and 5- to 50-fold decreases in plasma viremia, although suppression of viral replication was transient. Two of three treated monkeys developed antibody responses against the administered monoclonal antibody. Loss of antiviral effect was not temporally associated with anti-hu5A8 antibody responses or due to activation of CD4(+) T cells by hu5A8. However, SIV isolated after hu5A8 treatment was approximately 5-fold more resistant to suppression by hu5A8 than SIV isolates obtained from the same monkeys before treatment. The rapid development of resistance may have resulted from SIV variants that infect cells by a CD4-independent mechanism. These results support the overall concept of anti-CD4 monoclonal antibody treatment to suppress AIDS virus replication in vivo while demonstrating important issues as to its clinical feasibility.     

Pathogenesis of acute infection in rhesus macaques with a lymphocyte-tropic strain of simian immunodeficiency virus.

The simian immunodeficiency virus, SIVmac, causes disease affecting multiple organ systems in macaques similar to human immunodeficiency virus infection in humans. Molecularly cloned SIVmac with a strong lymphocyte tropism was used in pathogenesis experiments to correlate viral cell tropism with disease. In 5 animals, exhaustive analyses on viruses from tissues and identification of infected precursor cells were done at multiple times during infection to ensure the virus had not mutated into a macrophage-tropic variant. Viral replication was measured by infectivity, infectious center assays, and in situ hybridization. Lymphocytes produced most virus in tissues, indicating the virus maintained its cell tropism in vivo. Lymphocytes in bone marrow were latently infected and those in the spleen and lymph nodes were productively infected. The virus failed to replicate in the brain after intracerebral inoculation. SIVmac that maintained a strong tropism for lymphocytes and a corresponding poor tropism for macrophages can cause persistent infection and AIDS but not other diseases such as primary pneumonia and encephalitis in rhesus macaques.     

T cell chronic lymphocytic leukemia: presence in bone marrow and peripheral blood of cells that suppress erythropoiesis in vitro.

The pathogenesis of the anemia associated with malignancy was investigated in a patient with T cell chronic lymphocytic leukemia. The plasma clot culture system was used as a measure in vitro of erythropoiesis. The patient's peripheral blood and marrow T lymphocytes obtained both before and after transfusion therapy suppressed erythroid colony formation by normal human bone marrow cells. Pretreatment of the patient's bone marrow T cells by antithymocyte globulin (ATG) and complement reversed this suppression. In addition, pretreatment of the patient's marrow cells with ATG and complement markedly augmented erythropoiesis in vitro. The expression of erythroid activity caused by the selective destruction of the suppressor T lymphocytes in the patient's bone marrow with ATG and the suppression of normal erythropoiesis by the patient's bone marrow and peripheral blood lymphocytes suggest that interaction between the malignant T cell and the erythropoietin-responsive stem cell is important in production of anemia in this patient.     

Genetic and biological comparisons of pathogenic and nonpathogenic molecular clones of simian immunodeficiency virus (SIVmac).

Simian immunodeficiency virus (SIV) is a designation for a group of related but unique lentiviruses identified in several primate species. A viral isolate from a rhesus macaque (i.e., SIVmac) causes a fatal AIDS-like disease in experimentally infected macaques, and several infectious molecular clones of this virus have been characterized. This report presents the complete nucleotide sequence of molecularly cloned SIVmac1A11, and comparisons are made with the sequence of molecularly cloned SIVmac239. SIVmac1A11 has delayed replication kinetics in lymphoid cells but replicates as well as uncloned SIVmac in macrophage cultures. Macaques infected with virus from the SIVmac1A11 clone develop antiviral antibodies, but virus does not persist in peripheral blood mononuclear cells and no disease signs are observed. SIVmac239 infects lymphoid cells, shows restricted replication in cultured macrophages, and establishes a persistent infection in animals that leads to a fatal AIDS-like disease. Both viruses are about 98% homologous at the nucleotide sequence level. In SIVmac1A11, the vpr gene as well as the transmembrane domain of env are prematurely truncated, whereas the nef gene of SIVmac239 is prematurely truncated. Sequence differences are also noted in variable region 1 (V1) in the surface domain of the env gene. The potential implications of these and other sequence differences are discussed with respect to the phenotypes of both viruses. This animal model is critically important for investigating the roles of specific viral genes in viral/host interactions that cannot be studied in individuals infected with the human immunodeficiency virus (HIV).     

Sequential analysis of apoptosis induction in peripheral blood mononuclear cells and lymph nodes in the early phase of pathogenic and nonpathogenic SIVmac infection.

To investigate the role of apoptosis in the early phase of HIV infection, we used macaques infected with simian immunodeficiency virus strain mac (SIVmac) as a primate model and examined sequentially the characteristics of apoptosis of lymphocytes in peripheral blood mononuclear cells (PBMCs) and lymph nodes in the early phase of SIVmac infection. Five macaques infected with a pathogenic strain of SIV, SIVmac239, were analyzed during the first 4 weeks after infection. Peripheral CD4+ and CD8+ cells transiently decreased at 1 week postinfection. The percentage of apoptotic cells in cultured PBMCs increased from about 2 weeks postinfection. The number of apoptotic cells in lymph node sections was higher on days 13 and 28 postinfection than before infection and on day 5 postinfection. Fas antigen expression on peripheral lymphocytes was upregulated from day 8 postinfection. These results indicate that apoptosis is induced about 2 weeks after SIVmac239 infection, following the upregulation of Fas antigen expression on lymphocytes. Since apoptosis was induced about 1 week after the decrease in peripheral CD4+ and CD8+ cell counts, it appears that the apoptosis induction does not play an important role in the transient lymphopenia in the early phase of SIVmac infection. In macaques infected with a nonpathogenic derivative of SIVmac239, SIVmac delta nef, apoptosis of lymphocytes was induced as it was in SIVmac239-infected macaques, but to a lesser degree, suggesting a correlation between the extent of apoptosis induction in lymphocytes in the early phase of SIVmac infection and the pathogenicity of SIVmac.     

Generation of HIV-1 derivatives that productively infect macaque monkey lymphoid cells

The narrow host range of human immunodeficiency virus type 1 (HIV-1) is caused in part by innate cellular factors such as apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G (APOBEC3G) and TRIM5alpha, which restrict virus replication in monkey cells. Variant HIV-1 molecular clones containing both a 21-nucleotide simian immunodeficiency virus (SIV) Gag CA element, corresponding to the HIV-1 cyclophilin A-binding site, and the entire SIV vif gene were constructed. Long-term passage in a cynomolgus monkey lymphoid cell line resulted in the acquisition of two nonsynonymous changes in env, which conferred improved replication properties. A proviral molecular clone, derived from infected cells and designated NL-DT5R, was used to generate virus stocks capable of establishing spreading infections in the cynomolgus monkey T cell line and CD8-depleted peripheral blood mononuclear cells from five of five pig-tailed macaques and one of three rhesus monkeys. NL-DT5R, which genetically is >93% HIV-1, provides the opportunity, not possible with currently available SIV/HIV chimeric viruses, to analyze the function of multiple HIV-1 genes in a broad range of nonhuman primate species.     

Morphine promotes simian acquired immunodeficiency syndrome virus replication in monkey peripheral mononuclear cells: induction of CC chemokine receptor 5 expression for virus entry

Rhesus monkeys (Macaca mulatta) chronically administered opioids were more susceptible to simian immunodeficiency virus (SIV) strain mac239 (SIVmac239) infection than those without prior exposure to opioids. Increased plasma viremia in morphine-dependent monkeys allowed SIV to be detected in the animals' peripheral blood mononuclear cells (PBMC) without cocultivation with a tissue culture cell line. In contrast, virus titers from the PBMC of morphine-naive SIVmac239-infected animals were undetectable in the absence of cocultivation. PBMC isolated from noninfected animals and treated with morphine sulfate in vitro produced an increase in the expression of beta-chemokine receptor 5 (CCR5). Because both SIVmac239 and human immunodeficiency virus (HIV) require CCR5 for cell entry, the unique role of morphine in promoting SIV infection may provide a mechanism to account for the high incidence of HIV disease among drug-using populations.     

Macrophages as susceptible targets for HIV infection, persistent viral reservoirs in tissue, and key immunoregulatory cells that control levels of virus replication and extent of disease

Although macrophages are major targets for human immunodeficiency virus (HIV) infection in vivo, study of HIV-macrophage interactions in vitro was hindered because many laboratory strains of HIV would not replicate in macrophages, and because survival of macrophages in culture was poor. Addition of purified macrophage colony-stimulating factor (M-CSF) to cultured macrophages markedly improves their survival, but does not induce proliferation. HIV isolates that replicate in macrophages will also replicate in lymphocytes; however, isolates adapted to lymphoid cells (such as HIV-HTLVIIIB) will not replicate in macrophages. The envelope gene appears to be a major determinant of the cell tropism of viral isolates. T-cell grown virus stocks synthesize abundant gp120, while virus grown in macrophages contains relatively much less gp120. Electron microscopy of virions from macrophages shows them to be depleted of gp120 surface "spikes." Recombination studies show that the portion of the genome coding for the envelope glycoprotein appears to determine cell tropism. Lastly, rsCD4 neutralized macrophage-tropic isolates less efficiently than T-cell tropic isolates. HIV replication in macrophages is partially under the control of cellular factors, although these have been less well characterized than they have in lymphocytes.     

Human and rhesus macaque hematopoietic stem cells cannot be purified based only on SLAM family markers

Various combinations of antibodies directed to cell surface markers have been used to isolate human and rhesus macaque hematopoietic stem cells (HSCs). These protocols result in poor enrichment or require multiple complex steps. Recently, a simple phenotype for HSCs based on cell surface markers from the signaling lymphocyte activation molecule (SLAM) family of receptors has been reported in the mouse. We examined the possibility of using the SLAM markers to facilitate the isolation of highly enriched populations of HSCs in humans and rhesus macaques. We isolated SLAM (CD150(+)CD48(-)) and non-SLAM (not CD150(+)CD48(-)) cells from human umbilical cord blood CD34(+) cells as well as from human and rhesus macaque mobilized peripheral blood CD34(+) cells and compared their ability to form colonies in vitro and reconstitute immune-deficient (nonobese diabetic/severe combined immunodeficiency/interleukin-2 γc receptor(null), NSG) mice. We found that the CD34(+) SLAM population contributed equally or less to colony formation in vitro and to long-term reconstitution in NSG mice compared with the CD34(+) non-SLAM population. Thus, SLAM family markers do not permit the same degree of HSC enrichment in humans and rhesus macaques as in mice.     

Highly pathogenic SHIVs and SIVs target different CD4+ T cell subsets in rhesus monkeys, explaining their divergent clinical courses

In contrast to simian immunodeficiency viruses (SIVs), which induce immunodeficiency over a 1- to 3-year period, highly pathogenic simian-human immunodeficiency viruses (SHIVs) cause a complete, irreversible, and systemic depletion of CD4⁺ T lymphocytes in rhesus monkeys within weeks of infection. By using small-molecule competitors specific for CCR5 and CXCR4 in ex vivo assays, we found that highly pathogenic SHIV_DH12R exclusively uses CXCR4 for infection of rhesus peripheral blood mononuclear cells, whereas SIV_mac239 and SIV_smE543 use CCR5 for entry into the same cells. During the period of peak virus production in SHIV_DH12R- or SHIV_89.6P-infected rhesus monkeys, massive elimination of CXCR4⁺ naïve CD4⁺ T cells occurred. In contrast, circulating CCR5⁺ memory CD4⁺ T cells were selectively depleted in rapidly progressing SIV-infected monkeys. At the time of their death, two SIV rapid progressors had experienced a nearly complete loss of the memory CD4⁺ T cell subset from the blood and mesenteric lymph nodes. Thus, pathogenic SHIVs and SIVs target different subsets of CD4⁺ T cells in vivo, with the pattern of CD4⁺ T lymphocyte depletion being inextricably linked to chemokine receptor use. In the context of developing an effective prophylactic vaccine, which must potently control virus replication during the primary infection, regimens that suppress SHIVs might not protect monkeys against SIV or humans against HIV-1.Highly pathogenic simian-human immunodeficiency viruses (SHIVs) cause a rapid, systemic, and complete loss of CD4⁺ T lymphocytes within weeks of inoculation of rhesus monkeys, high and sustained levels (>10⁷ copies per ml of plasma) of viral RNA, and death from immunodeficiency in 12–30 weeks (1–3). This rapid and irreversible CD4⁺ T cell-depleting phenotype is markedly different from that observed for either simian immunodeficiency virus (SIV) or HIV-1, both of which generally induce more gradual and moderate losses of CD4⁺ T cells, and much slower development of clinical disease in macaques and humans, respectively. Surprisingly, SHIVs have proven to be more controllable by the same vaccine regimens that are ineffective against SIV (4–7). Vaccine strategies that readily and durably suppress plasma SHIV RNA levels and prevent the associated global loss of CD4⁺ T lymphocytes only transiently control SIV viral load, and SIV-challenged macaques invariably succumb to AIDS after similar immunizations.The distinctive features of in vivo SHIV and SIV infections enumerated above suggest that the underlying mechanism(s) of disease induction by each virus may be different. Side-by-side comparisons of CD4⁺ T cell subsets targeted by SHIVs and SIV during infections of rhesus monkeys were therefore carried out. In the case of SIV, four (of the 10 initially inoculated) rapidly progressing animals were studied because they exhibit virological parameters and clinical symptoms that are similar to those reported for macaques infected with SHIVs (8). Ex vivo experiments, employing competitors specific for CCR5 and CXCR4, revealed that SIVs exclusively used CCR5 to enter and spread through cultured rhesus monkey peripheral blood mononuclear cells (PBMCs), whereas SHIV_DH12R used CXCR4, but not CCR5, during productive infections of the same cells. In inoculated rhesus monkeys, massive depletion of naïve CD4⁺ T lymphocytes was observed during the period of peak SHIV production (weeks 1 to 3). In contrast, memory CD4⁺ T cells were selectively eliminated from the blood and lymph nodes in rapidly progressing SIV-infected animals. The expression of CXCR4 on virtually all naïve and a significant fraction of memory CD4⁺ T lymphocytes ultimately makes both subsets the target of highly pathogenic SHIVs, and explains the rapid, irreversible, and complete depletion of CD4⁺ T cells in SHIV, but not SIV infections of macaques.     

Pathologic features of SIV-induced disease and the association of macrophage infection with disease evolution.

Since the original isolation of simian immunodeficiency virus (SIV) from a macaque with an AIDS-like disease, numerous studies have demonstrated the close biologic and genetic relationship of the SIVs to the HIVs. Probably most important, the clinical spectrum of disease associated with SIVmac/SIVsmm infection in rhesus monkeys is strikingly similar to AIDS in HIV-1-infected human beings. Herein are summarized the pathologic features of SIVmac-induced disease in a cohort of rhesus monkeys, with special reference to the role of infected macrophages in the development of AIDS-related manifestations.