Early Control of Highly Pathogenic Simian Immunodeficiency Virus/Human Immunodeficiency Virus Chimeric Virus Infections in Rhesus Monkeys Usually Results in Long-Lasting Asymptomatic Clinical Outcomes

Abstract

In contrast to simian immunodeficiency viruses (SIVs), which induce immunodeficiency over a 1-to 2-year period, highly pathogenic simian-human immunodeficiency viruses (SHIVs) cause an irreversible and systemic depletion of CD4 ؉ T lymphocytes in macaque monkeys within weeks of inoculation. Nonetheless, the seemingly more aggressive SHIVs have proven to be easier to control by the same vaccine regimens which fail to contain SIV. Because early events during in vivo infections may determine both the pathogenic consequences of the challenge virus and its sensitivity to interventions that prevent disease, we have evaluated the effects of inoculum size and a potent antiretroviral drug on the development of disease in monkeys infected with SHIV DH12R . The results obtained show that in a majority of inoculated animals, suppression of SHIV replication during the first 2 weeks of infection, which prevents complete loss of CD4 ؉ T cells, leads to very low to undetectable postpeak viremia and an asymptomatic clinical course for periods up to 4 years.

CD8+and CD20+Lymphocytes Cooperate To Control Acute Simian Immunodeficiency Virus/Human Immunodeficiency Virus Chimeric Virus Infections in Rhesus Monkeys: Modulation by Major Histocompatibility Complex Genotype

“…For example, when potent antiretroviral therapy is initiated in rhesus monkeys within 24 h of SIV inoculation, plasma viremia is markedly suppressed during or following cessation of treatment (22). A similar 28-day treatment regimen, begun on day 5 postinoculation in SIV/HIV chimeric virus (SHIV)-infected animals, resulted in durable suppression of virus replication in three of four treated macaques and a 4-year disease-free clinical course (14). Passive transfer of high-titer monoclonal or polyclonal neutralizing antibodies prior to SHIV challenge can also successfully abort the primary virus infection and in several instances resulted in sterilizing protection (24,34,37,46).…”

“…In addition, genetic determinants affecting major histocompatibility complex (MHC) class I alleles (17,28,30,31,35), chemokines (11,50), and chemokine receptors (7,23,41,47) have been shown to alter the balance between susceptibility/resistance to both HIV-1 and other primate lentiviruses. The dose dependency of the full-blown SHIV-induced immunodeficiency syndrome (rapid and complete depletion of CD4 ϩ T lymphocytes within weeks of virus inoculation was observed with large, but not small [Ͻ625 50% tissue culture infective doses {TCID 50 }], virus inocula [9]) is yet another illustration of the race between vigorous SHIV replication/systemic dissemination and containment by effective host responses (9,14).…”

Generation of the Pathogenic R5-Tropic Simian/Human Immunodeficiency Virus SHIV AD8 by Serial Passaging in Rhesus Macaques

“…HeLa cells were transfected with 25 g of pSHIV AD8 , and the virus present in the supernatant at 48 h was pelleted in an ultracentrifuge and resuspended in RPMI 1640 medium as previously described (52). Stocks of the cloned SHIV AD8 were prepared by infecting PM1 cells (31) or concanavalin A (ConA)-activated rhesus monkey peripheral blood mononuclear cells (PBMC) with the HeLa-derived SHIV AD8 , as previously described (23,24), and pooling the supernatant media at the times of peak reverse transcriptase (RT) production from both infections. SHIV AD8 stock 2 (SHIV AD8#2 ) was prepared from PBMC and bone marrow (BM), spleen, and lymph node (LN) samples collected from macaque CK1G on day 6 p.i.…”

AIDS Vaccines and Preexposure Prophylaxis: Is Synergy Possible?

“…15 Animal studies have provided evidence that PrEP and postexposure prophylaxis (PEP) with tenofovir disoproxil fumarate (TDF), alone or in combination with emtricitabine (FTC), can protect against simian immunodeficiency virus (SIV) and chimeric simian HIV (SHIV) infection. [16][17][18][19][20][21][22] Furthermore, in some experiments, animals that became infected despite receiving TDF as PrEP or PEP showed delayed onset of viremia and delayed seroconversion, 18,20,23 demonstrating that even in the case of incomplete protection against infection, PrEP or PEP may lead to attenuated acute infection (perhaps by allowing the immune system to gain some control of the virus). The demonstrated efficacy of TDF in the treatment of HIV infection, the lack of reported serious safety problems associated with its use, 24 its long halflife, [25][26][27][28] and its relatively high threshold to drug resistance 29 make this antiretroviral agent an attractive candidate for systemic or topical prophylactic use.…”