Protection from secondary human immunodeficiency virus type 1 infection in chimpanzees suggests the importance of antigenic boosting and a possible role for cytotoxic T cells.

Recent evidence suggests a much higher prevalence of human immunodeficiency virus type 1 (HIV-1) recombinants than previously anticipated. These recombinants arise from secondary HIV infections in individuals already infected with the virus. It remains unclear why some individuals acquire secondary HIV-1 infections and others do not. To address this question, a study was undertaken of a small cohort of chimpanzees with well-defined HIV-1 infection. After exposure to an infectious dose of heterologous primary isolate, 4 of 8 HIV-1 seropositive chimpanzees resisted secondary infection, whereas 2 naive controls became readily infected. Only animals who were immunologically boosted were protected. Protection from heterologous secondary exposure appeared to be related to the repertoire of the cytolytic CD8(+) T cell responses to HIV-1. Data suggested that immunologic boosting by HIV-1 antigens or exposure to subinfectious doses of virus may be important events in sustaining sufficient immunity to prevent secondary infections from occurring.

Conserved CTL epitopes shared between HIV-infected human long-term survivors and chimpanzees.

Certain HIV-1 infected humans that do not progress to AIDS have been documented to share particular MHC class I alleles that appear to correlate with long-term survival. HIV-1-infected chimpanzees are relatively resistant to progression to AIDS. Out of a group of 10 chimpanzees with CTL activity and nonprogressive HIV-1 infection, 2 animals with prominent cytolytic CD3+CD8+ T cell responses to HIV-1 Ags were studied in detail. Characterization of these CTL revealed that they contained the granzymes A and B, T cell intracellular Ag-1, and perforin and induced calcium-dependent cytolysis that correlated with the presence of apoptotic nuclei in target cells. These CTL responses were directed against two gagpeptides, which were found to be identical to previously described epitopes recognized in the context of HLA-B27 and HLA-B57 molecules. The latter two restriction elements occur with increased frequency in human long-term survivor cohorts. Phylogenetic comparisons revealed that the chimpanzee restriction elements, Patr-B*02and -B*03, described here do not show any obvious similarity with the HLA-B*27 and -B*57 alleles, suggesting that CTL responses to HIV-1 in distinct primate species may be controlled by different types of HLA-B-like molecules. The CTL responses in these two chimpanzees are directed, however, against highly conserved epitopes mapping across the majority of HIV-1 clades.

Cytotoxic T cells and neutralizing antibodies induced in rhesus monkeys by virus-like particle HIV vaccines in the absence of protection from SHIV infection.

HIV Pr55gag has in the absence of other viral components the capacity to self assemble in budding noninfectious virus-like particles (VLP). The immunological spectrum of the HIV-1IIIB gag-derived VLP was expanded either by stable anchoring of chimeric modified gp 120 on the surface of the VLP (type 1) or by replacing sequences of the Pr55gag precursor by the V3 loop and a linear portion of the CD4 binding domain (type 2). This noninfectious antigen delivery system was evaluated for immunogenicity and efficacy in rhesus macaques without adjuvants. Intramuscular immunization with both types of VLP induced high titers of gag-specific antibodies ranging from 1/8000 to 1/510,000 for type 1 VLP and from 1/4000 to 1/16,000 for type 2 VLP. Only animals immunized with type 1 VLP developed substantial endpoint titers of env-specific antibodies (1/2000-1/32,000) with a neutralizing capacity at serum dilutions of 1/32-1/128. Gag- and env-specific cytotoxic T lymphocyte (CTL) activity was induced by both types of VLP at similar levels. Four weeks after the last immunization animals were challenged intravenously with 20 MID50 of the cell free homologous envelope simian/HIV-1IIIB chimeric challenge stock Despite HIV-1-specific neutralizing and CTL responses, all vaccinated animals became infected.

Characteristics of primary infection of a European human immunodeficiency virus type 1 clade B isolate in chimpanzees.

The aim of the study was to select, from a panel of candidate European human immunodeficiency virus type 1 (HIV-1) clade B primary virus isolates, one isolate based on replication properties in chimpanzee peripheral blood mononuclear cells (PBMC). Secondly, to evaluate the in vivo kinetics of primary infection of the selected isolate at two different doses in two mature, outbred chimpanzees (Pan troglodytes). Four different low passage, human PBMC-cultured 'primary' HIV-1 isolates with European clade B consensus sequence were compared for their ability to replicate in vitro in chimpanzee versus human PBMC. The isolate which yielded the highest titre and most vigorous cytopathic effect in chimpanzee PBMC was evaluated for coreceptor usage and chosen for evaluation in vivo. Only the HIV-1Han2 isolate replicated in chimpanzee PBMC in vitro at detectable levels. This isolate was demonstrated to utilize CCR4, CCR5 and CXCR4 coreceptors and could be inhibited by beta-chemokines. Infection of chimpanzees was demonstrated by viral RNA and DNA PCR analysis, both in plasma as well as in PBMC and lymph node cells as early as 3 weeks after inoculation. Antibodies developed within 6 weeks and continued to increase to a maximum titre of approximately 12800, thereafter remaining in this range over the follow-up period of 2 years. Compared to cell line-adapted HIV-1 isolates there were slight but no dramatic differences in the kinetics of infection of chimpanzees with this particular primary isolate.