The use of a tenofovir-containing vaginal microbicide gel for the prevention of HIV-1 infection in sexually active, HIV-1-uninfected adult women in KwaZulu-Natal, South Africa showed a significant reduction of HIV-1 infection rates by 39% in the primary intent-to-treat analysis 1
. Here, we examined the innate and adaptive immune responses in women with breakthrough HIV-1 infection that either used tenofovir microbicide gel or were part of the placebo arm. The frequencies and activation status of principal effector cells of the innate immune response, including NK cells and mDCs, assessed within 3 months of HIV-1 infection were not affected by the use of the tenofovir gel. Previous studies have demonstrated a significant expansion of NK cells in infected individuals during the early phase of HIV-1 infection, and a subsequent contraction of NK cell and mDC populations 9-11
. We can therefore not exclude that NK cell and mDC frequencies in the initial three months of infection might have been affected by the use of the tenofovir gel, and that these changes in innate effector cells might have subsequently contributed to the observed functional differences in HIV-1-specific CD4+ T cells 12
HIV-1-specific T cells are considered critical for the control of HIV-1 replication and disease progression 8, 13-15
. While HIV-1-specific CD8+ T cell responses to both Gag and Nef peptides did not significantly differ between the groups, HIV-1 Gag-specific IFN-γ+ CD4+ T cell responses were significantly higher in women in the tenofovir gel arm compared to the placebo arm. HIV-1-specific CD4+ T cell responses are rapidly lost following acute infection in the presence of continuing HIV-1 replication, and this is in contrast to HIV-1-specific CD8+ T cell frequencies, which tend to increase over at least the first year of HIV-1 infection with continues exposure to antigen 16-20
. Previous studies have shown that CD4+ T cells, and in particular gut-associated CD4+ T cells are severely depleted within the first few days/weeks of infection 21
and that HIV-1 preferentially infects HIV-1-specific CD4+ T cells 22
. The presence of an antiretroviral agent, such as tenofovir, during this crucial period might protect CD4+ T cells from deletion, allowing for a preservation of HIV-1-specific IFN-γ CD4+ T cells. The observation that women receiving tenofovir gel maintained higher Gag-specific CD4+ T cell responses despite the reported lack of differences in viral load set-point between tenofovir gel and placebo recipients 1 was however unexpected, and the long-term clinical benefit of this preservation, and its consequences for HIV-1-specific immune function, will require further investigation.
Taken together, our studies in a subset of women who experienced breakthrough HIV-1 infection despite randomization to tenofovir gel usage demonstrate no significant alteration in the frequencies and activation status of key innate immune cells and HIV-1-specific CD8+ T cell responses three months following infection. However, tenofovir gel applied vaginally around the time of HIV-1 transmission might protect HIV-1-specific CD4+ T cell responses in infected individuals. This study demonstrates for the first time that the use of vaginal microbicides containing antiretroviral drugs can modulate HIV-1-specific immunity in individuals with breakthrough infection. These consequences of microbicide use for immune responses in individuals that acquire HIV-1 have to be considered in the design of future trials that will combine microbicides with HIV-1 vaccines.