Acute Effects of Pathogenic Simian-Human Immunodeficiency Virus Challenge on Vaccine-Induced Cellular and Humoral Immune Responses to Gag in Rhesus Macaques

Abstract

Simian-human immunodeficiency virus (SHIV) infection in macaques provides a convenient model for testing vaccine efficacy and for understanding viral pathogenesis in AIDS. We immunized macaques with recombinant, Salmonella typhimurium (expressing Gag) or soluble Gag in adjuvant to generate T-cell-dependent lymphoproliferative or serum antibody responses. Immunized animals were challenged by intrarectal inoculation with SHIV89.6PD. Virus infection was accompanied by rapid losses of lymphoproliferative responses to Gag or phytohemagglutinin. By 8 weeks, mitogen responses recovered to near normal levels but antigen-specific immunity remained at low or undetectable levels. Serum antibody levels were elevated initially by virus exposure but soon dropped well below levels achieved by immunization. Our studies show a rapid depletion of preexisting Gag-specific CD4+ T cells that prevent or limit subsequent antiviral cellular and humoral immune responses during acute SHIV infection.

Lymphocyte Activation during Acute Simian/Human Immunodeficiency Virus SHIV89.6PDInfection in Macaques

“…In a previous study, we observed loss of proliferative responses to p27 and PHA as early as 1 week after i.r. SHIV 89.6PD infection in p27-immunized rhesus macaques; depressed mitogen responses were transient and returned to normal levels by 8 weeks after infection, while proliferative responses to Gag antigen did not recover (31). Similar observations of transient lymphocyte unresponsiveness were reported in HIV-1 ϩ persons during acute retroviral syndrome (5,22).…”

“…In our experience, i.r. doses of 2,500 tissue culture-infective doses (TCID) or higher produce a persistent infection in Ͼ95% of animals and we have not detected any outcomes consistent with transient viremia (29,31).…”

“…Mononuclear cell preparations from the blood, LN, and spleen were tested for proliferative responses to simian immunodeficiency virus capsid protein p27 and to the mitogen PHA. p27-specific proliferative responses were not detected in any macaque samples from these early time points after infection (data not shown) by the same assay that detected antigenspecific lymphoproliferation in immunized macaques (31). It was surprising that proliferative responses to PHA were low or absent in lymphocytes of the blood, LN, and spleen from animal 94089 by 8 days after i.v.…”

Blood–brain barrier disruption in simian immunodeficiency virus encephalitis

“…SHIV89.6 is a hybrid pathogenic SIV isolate containing the HIV‐1 89.6 envelope protein. Ongoing transmission studies for SHIV89.6 include protocols for serial sacrifices at 3–14 days after intravenous, rectal or vaginal inoculation, as well as long‐term infection studies after rectal inoculation [43,44,47]. SIVppm is an animal passage of the SIVmac251 isolate, and has similar pathogenetic properties to the original viral isolate.…”

Vaccination with Tat toxoid attenuates disease in simian/HIV-challenged macaques

“…Further, we have been able to show changes in IFN-␣ production and chemokine receptor expression in immunized and challenged animals, as evidence that these effects of Tat protein that were known from in vitro studies are important parts of the viral pathogenesis mechanism in SHIV-challenged macaques. (24,25). Methods for mucosal inoculation were described previously (26).…”