Differences in HIV-2 plasma viral load and immune activation in HIV-1 and HIV-2 dually infected persons and those infected with HIV-2 only in Abidjan, Côte D'Ivoire.

OBJECTIVE: To determine whether blood plasma levels of HIV-2 RNA viral loads and immune activation markers differ between persons infected with HIV-2 only and those dually infected with HIV-1 and HIV-2. METHODS: Between September 1996 and February 2000, we collected, analyzed and compared levels of HIV-2 RNA in plasma and immune activation markers among 52 persons infected with HIV-2 alone and 75 with confirmed dual infection. We also compared viral load and immune activation in patients who were infected with HIV-1 only and those who were dually infected. RESULTS: When we conducted a CD4 T-cell count-stratified multivariate analysis of HIV-2 viral load, controlling for difference in CD4 T-cell counts, age and sex: at < 200 x 10 CD4 T cells/l, HIV-2 viral load was 2.0 log10 copies/ml lower in dually infected patients than in HIV-2 only patients (P < 0.0001). At CD4 T-cell counts between 200 x 10 and 500 x 10/l, HIV-2 viral load was 0.3 log10 copies/ml lower in dually infected patients (P = 0.45). However, at CD4 T-cells counts > 500 x 10/l, HIV-2 viral load was 0.9 log10 copies/ml higher in dually infected patients (P < 0.0001). Dually infected persons with undetectable HIV-2 viral loads had significantly higher median levels of CD8 T cells expressing CD38 (P < 0.001) and HLA-DR (P = 0.01) than HIV-2 only infected patients. CONCLUSION: These results suggest that in dual infection, the level of HIV-2 replication depends on the immune status of the patients, with HIV-1 out-replicating HIV-2 as disease progress.

Absence of SHIV infection in gut and lymph node tissues in rhesus monkeys after repeated rectal challenges following HIV-1 DNA/MVA immunizations.

We reported previously the absence of systemic infection in a subset of macaques vaccinated with an HIV-1 DNA/MVA vaccine after 18 or more rectal challenges with low (physiologically relevant) doses of SHIV162P3. To further study the apparent protection, we looked for sequestered virus in gut tissues, lymph nodes, spleen, and testes obtained at necropsy using virus co-culture and nested PCR for SIV Gag, Pol and LTR. There was no evidence of sequestered virus in tissues obtained from the four protected macaques. In contrast, at least one tissue from each of 11 infected animals scored positive by one of these sensitive procedures. Activated PBMC from the protected macaques were not inherently resistant to in vitro infection by the challenge virus. These findings demonstrate that some vaccinated macaques appeared to be free from the challenge virus. Therefore, such T cell-based vaccines may provide some protection when challenge virus doses approach physiological equivalencies.

Chemoprophylaxis with tenofovir disoproxil fumarate provided partial protection against infection with simian human immunodeficiency virus in macaques given multiple virus challenges.

We examined the efficacy of tenofovir disoproxil fumarate (TDF) in blocking simian human immunodeficiency virus (SHIV) infection in Chinese rhesus macaques. Once weekly for 14 weeks or until a macaque became infected, 12 male macaques were inoculated intrarectally with amounts of SHIV(SF162P3) (10 median tissue culture infective doses; 3.8 x 10(5) virus particles) that were approximately 5-fold higher than the human immunodeficiency virus type 1 RNA levels noted in human semen during an acute infection. Of the 12 macaques, 4 received oral TDF daily, 4 received oral TDF once weekly, and 4 (control animals) received no TDF. The control animals became infected after receiving a median of 1.5 virus inoculations; macaques receiving TDF daily (1 macaque remained uninfected after 14 inoculations) and those receiving TDF weekly became infected after a median duration of 6.0 and 7.0 weeks, respectively. Although infection was delayed in treated macaques, compared with control macaques, the differences were not statistically significant (P=.315); however, the study was limited by the small numbers of animals evaluated and the variability in blood levels of TDF that resulted from oral dosing. These data demonstrate that treatment with oral TDF provided partial protection against SHIV infection but ultimately did not protect all TDF treated animals against multiple virus challenges.

HIV-1 DNA/MVA vaccination reduces the per exposure probability of infection during repeated mucosal SHIV challenges.

Historically, HIV vaccines specifically designed to raise cellular immunity resulted in protection from disease progression but not infection when tested in monkeys challenged with a single high virus exposure. An alternative approach, more analogous to human sexual exposures, is to repetitively challenge immunized monkeys with a much lower dose of virus until systemic infection is documented. Using these conditions to mimic human sexual transmission, we found that a multi-protein DNA/MVA HIV-1 vaccine is indeed capable of protecting rhesus monkeys against systemic infection when repeatedly challenged with a highly heterologous immunodeficiency virus (SHIV). Furthermore, this repetitive challenge approach allowed us to calculate per-exposure probability of infection, an observed vaccine efficacy of 64%, and undertake a systematic analysis for correlates of protection based on exposures needed to achieve infection. Therefore, improved non-human primate models for vaccine efficacy can provide novel insight and perhaps renew expectations for positive outcomes of human HIV clinical trials.