CD4 ⁺ -T-Cell and CD20 ⁺ -B-Cell Changes Predict Rapid Disease Progression after Simian-Human Immunodeficiency Virus Infection in Macaques

Abstract

Simian-human immunodeficiency virus 89.6PD (SHIV89.6PD) was pathogenic after intrarectal inoculation of rhesus macaques. Infection was achieved with a minimum of 2,500 tissue culture infectious doses of cell-free virus stock, and there was no evidence for transient viremia in animals receiving subinfectious doses by the intrarectal route. Some animals experienced rapid progression of disease characterized by loss of greater than 90% of circulating CD4+ T cells, sustained decreases in CD20+ B cells, failure to elicit virus-binding antibodies in plasma, and high levels of antigenemia. Slower-progressing animals had moderate but varying losses of CD4+ T cells; showed increases in circulating CD20+ B cells; mounted vigorous responses to antibodies in plasma, including neutralizing antibodies; and had low or undetectable levels of antigenemia. Rapid progression led to death within 30 weeks after intrarectal inoculation. Plasma antigenemia at 2 weeks after inoculation (P ≤ 0.002), B- and T-cell losses (P ≤ 0.013), and failure to seroconvert (P ≤ 0.005) were correlated statistically with rapid progression. Correlations were evident by 2 to 4 weeks after intrarectal SHIV inoculation, indicating that early events in the host-pathogen interaction determined the clinical outcome.

Insufficient Production and Tissue Delivery of CD4+Memory T Cells in Rapidly Progressive Simian Immunodeficiency Virus Infection

“…SIV Coreceptor Tropism, Patterns of CD4 ϩ T Cell Depletion, and Early Disease Progression. Although total peripheral blood CD4 counts have long been the benchmark of immunologic assessment of disease progression in both HIV and SHIV infection (1,2,31,32), this parameter was not predictive of early pathogenesis in the SIV-infected RMs studied here ( Fig. 1 B).…”

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

“…Animals 011, 015, and 058 (Tat toxoid alone) all had strong CMI and antibody responses to Tat before challenge, and their CD4 T cell counts remained in the normal range (averaging 48% of the starting CD4 T cell count) even by 8 weeks after infection. Animal 061 in this same group had moderate immune responses to Tat before challenge and still managed to maintain 14% of the starting CD4 T cell count by 8 weeks after infection, a level above the threshold for slow progressors, according to previously published criteria (25). Unimmunized control macaques all experienced sharp drops in the CD4 ϩ T cell count (Fig.…”

“…We tested whether immunization could protect against infection or attenuate disease progression. As our endpoints, we selected plasma viral RNA copies, p27 antigenemia, and CD4 T cell counts that are known to be correlated with progression (25). We also included circulating IFN-␣ levels and chemokine receptor expression; these markers are linked to disease progression and are triggered by Tat in vitro (8,9,11).…”

“…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).…”

Factors Associated with Slow Disease Progression in Macaques Immunized with an Adenovirus-Simian Immunodeficiency Virus (SIV) Envelope Priming-gp120 Boosting Regimen and Challenged Vaginally with SIVmac251

“…Primary-isolate neutralization and the development of a mature antibody response have also been correlated with protection of macaques against SIV infection (13,67). In contrast, macaques unable to mount an antibody response follow-ing exposure to SIV or SHIV quickly develop virulent infections and progress rapidly to AIDS and death (40,61,63). Both immunized macaques exhibited significant CTL activity following the reboost.…”