Genital Tract Inflammation During Early HIV-1 Infection Predicts Higher Plasma Viral Load Set Point in Women

In sub-Saharan Africa, which has the highest prevalence of human immunodeficiency virus type 1 (HIV-1) worldwide, most new infections occur by sexual transmission to women [1]. The genital mucosa is the initial site of viral replication following vaginal transmission of HIV-1 in women and simian immunodeficiency virus (SIV) in rhesus macaques [2, 3]. In macaques, vaginal inoculation with SIV is followed by proinflammatory cytokine production and recruitment of CD4+ T cells that are necessary for local viral expansion and dissemination to the systemic compartment [4–6]. Proinflammatory cytokine expression in the genital mucosa correlates with viral replication and approaches baseline as peak SIV viremia declines [6]. HIV-1 infection may likewise be accompanied by an early inflammatory cascade in the genital tract that is associated with viral replication in this compartment. HIV-1 has been shown to directly induce inflammatory cytokine production via Toll-like receptor 7 and 8 activation [7]. Elevated concentrations of inflammatory cytokines in turn may upregulate HIV-1 replication by recruiting and activating target cells and through NF-κB activation [4, 8–11]. Several studies have shown that cervicovaginal proinflammatory cytokines are upregulated in women with early or chronic HIV-1 infection compared with HIV-uninfected women [10, 12–16]. However this upregulation may be attributed to the high frequency of sexually transmitted infections (STIs) or bacterial vaginosis (BV) in these individuals rather than HIV-1 itself [17]. For example, BV was associated with increased concentrations of proinflammatory interleukin (IL)–1β, whereas chronic HIV-1 infection was not [18]. HIV-1 shedding, which is associated with STIs [19], may induce further inflammatory cytokine production. Plasma cytokine concentrations during early HIV-1 infection are predictive of plasma viral load set points and CD4 depletion [20], and treatment with cytokines such as IL-12p70 and IL-15 during acute SIV infection is associated with altered disease course in macaques [21–23]. Several studies have suggested that cytokine responses in the genital tract during the early stages of HIV-1 infection may likewise be associated with disease progression. In macaques, induction of inflammatory cytokines and immune cell influx into the genital tract prior to vaginal SIV inoculation was associated with increased plasma viral load set points [24]. This suggests that preexisting genital inflammation in humans may similarly influence HIV-1 disease progression. Zara et al [14] demonstrated that upregulation of IL-1β in the genital tracts of HIV-1–infected women was associated with increased plasma viral loads. Recently, we reported that elevated proinflammatory cytokines in cervicovaginal lavage (CVL) correlated with lower blood CD4+ T-cell counts during early HIV-1 infection [15]. In this study, the relationships between genital cytokine concentrations during early HIV-1 infection and plasma viral load set point and blood CD4+ T-cell counts 12 months postinfection were investigated.