ABSTRACT
Simian immunodeficiency virus (SIV)-infected African nonhuman primates do not progress to AIDS in spite of high and persistent viral loads (VLs). Some authors consider the high viral replication observed in chronic natural SIV infections to be due to lower anti-SIV antibody titers than those in rhesus macaques, suggesting a role of antibodies in controlling viral replication. We therefore investigated the impact of antibody responses on the outcome of acute and chronic SIVagm replication in African green monkeys (AGMs). Nine AGMs were infected with SIVagm.sab. Four AGMs were infused with 50 mg/kg of body weight anti-CD20 (rituximab; a gift from Genentech) every 21 days, starting from day -7 postinfection up to 184 days. The remaining AGMs were used as controls and received SIVagm only. Rituximab-treated AGMs were successfully depleted of CD20 cells in peripheral blood, lymph nodes (LNs), and intestine, as shown by the dynamics of CD20+ and CD79a+ cells. There was no significant difference in VLs between CD20-depleted AGMs and control monkeys: peak VLs ranged from 10(7) to 10(8) copies/ml; set-point values were 10(4) to 10(5) SIV RNA copies/ml. Levels of acute mucosal CD4+ T-cell depletion were similar for treated and nontreated animals. SIVagm seroconversion was delayed for the CD20-depleted AGMs compared to results for the controls. There was a significant difference in both the timing and magnitude of neutralizing antibody responses for CD20-depleted AGMs compared to results for controls. CD20 depletion significantly altered the histological structure of the germinal centers in the LNs and Peyer's patches. Our results, although obtained with a limited number of animals, suggest that humoral immune responses play only a minor role in the control of SIV viral replication during acute and chronic SIV infection in natural hosts.
Subject(s)
B-Lymphocytes/immunology , Lymphocyte Depletion , Monkey Diseases/immunology , Simian Acquired Immunodeficiency Syndrome/immunology , Simian Acquired Immunodeficiency Syndrome/physiopathology , Simian Immunodeficiency Virus/pathogenicity , Virus Replication , Acute Disease , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Murine-Derived , Antibodies, Viral/administration & dosage , Antibodies, Viral/immunology , Antigens, CD20/metabolism , Chlorocebus aethiops , Chronic Disease , Flow Cytometry , Immunologic Factors/administration & dosage , Lymphocyte Activation , Monkey Diseases/pathology , Monkey Diseases/virology , Rituximab , Simian Acquired Immunodeficiency Syndrome/virology , Simian Immunodeficiency Virus/immunology , Simian Immunodeficiency Virus/physiologyABSTRACT
Simian immunodeficiency virus SIVrcm, which naturally infects red-capped mangabeys (RCMs), is the only SIV that uses CCR2 as its main coreceptor due to the high frequency of a CCR5 deletion in RCMs. We investigated the dynamics of SIVrcm infection to identify specific pathogenic mechanisms associated with this major difference in SIV biology. Four pigtailed macaques (PTMs) were infected with SIVrcm, and infection was monitored for over 2 years. The dynamics of in vivo SIVrcm replication in PTMs was similar to that of other pathogenic and nonpathogenic lymphotropic SIVs. Plasma viral loads (VLs) peaked at 10(7) to 10(9) SIVrcm RNA copies/ml by day 10 postinoculation (p.i.). A viral set point was established by day 42 p.i. at 10(3) to 10(5) SIVrcm RNA copies/ml and lasted up to day 180 p.i., when plasma VLs decreased below the threshold of detection, with blips of viral replication during the follow-up. Intestinal SIVrcm replication paralleled that of plasma VLs. Up to 80% of the CD4(+) T cells were depleted by day 28 p.i. in the gut. The most significant depletion (>90%) involved memory CD4(+) T cells. Partial CD4(+) T-cell restoration was observed in the intestine at later time points. Effector memory CD4(+) T cells were the least restored. SIVrcm strains isolated from acutely infected PTMs used CCR2 coreceptor, as reported, but expansion of coreceptor usage to CCR4 was also observed. Selective depletion of effector memory CD4(+) T cells is in contrast with predicted in vitro tropism of SIVrcm for macrophages and is probably due to expansion of coreceptor usage. Taken together, these findings emphasize the importance of understanding the selective forces driving viral adaptation to a new host.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , HIV Infections/immunology , Receptors, CCR2/immunology , Receptors, HIV/immunology , Simian Acquired Immunodeficiency Syndrome/immunology , Simian Immunodeficiency Virus/physiology , Animals , CD4-Positive T-Lymphocytes/virology , Cells, Cultured , Disease Models, Animal , Gene Expression , HIV/physiology , HIV Infections/virology , Humans , Leukocytes, Mononuclear/metabolism , Leukocytes, Mononuclear/virology , Macaca nemestrina , Molecular Sequence Data , Receptors, CCR2/genetics , Receptors, CCR4/genetics , Receptors, CCR4/immunology , Receptors, HIV/genetics , Simian Acquired Immunodeficiency Syndrome/genetics , Simian Acquired Immunodeficiency Syndrome/virology , Simian Immunodeficiency Virus/genetics , Simian Immunodeficiency Virus/immunology , Viral Load , Virus Internalization , Virus ReplicationABSTRACT
We investigated the impact of rhesus macaque (RM) B-cell depletion before inoculation with the isolate SIVsmmD215. Seven RMs were treated every 3 weeks with 50 mg/kg of an anti-CD20 antibody (rituximab) starting 7 days before inoculation for 2 (n = 4) and 5 (n = 3) months. Four control animals received no antibody. Three animals were completely depleted of CD20(+) B cells, but 4 were only partially depleted of CD20 cells in the LNs and intestine. The decrease in antibody production was consistent with the efficacy of tissue CD20 depletion. Seroconversion and neutralizing antibody production was significantly delayed in animals showing complete tissue CD20 depletion and remained at low titers in all CD20-depleted RMs. Surprisingly, there was no significant difference in acute or chronic viral loads between CD20-depleted and control animal groups. There was a tendency for lower viral set points in CD20-depleted animals. At 6 weeks after inoculation, cellular immune responses were significantly stronger in CD20-depleted animals than in controls. There was no significant difference in survival between CD20-depleted and control animals. Our data suggest that a deficiency of Ab responses did not markedly affect viral replication or disease progression and that they may be compensated by more robust cellular responses.