Mucosal Th17 cells play an important role in maintaining gut epithelium integrity and thus prevent microbial translocation. Chronic HIV infection is characterized by mucosal Th17 cell depletion, microbial translocation and subsequent immune-activation, which remain elevated despite antiretroviral therapy (ART) correlating with increased mortality. However, when Th17 depletion occurs following HIV infection is unknown. We analyzed mucosal Th17 cells in 42 acute HIV infection (AHI) subjects (Fiebig (F) stage I-V) with a median duration of infection of 16 days and the short-term impact of early initiation of ART. Th17 cells were defined as IL-17+ CD4+ T cells and their function was assessed by the co-expression of IL-22, IL-2 and IFNγ. While intact during FI/II, depletion of mucosal Th17 cell numbers and function was observed during FIII correlating with local and systemic markers of immune-activation. ART initiated at FI/II prevented loss of Th17 cell numbers and function, while initiation at FIII restored Th17 cell numbers but not their polyfunctionality. Furthermore, early initiation of ART in FI/II fully reversed the initially observed mucosal and systemic immune-activation. In contrast, patients treated later during AHI maintained elevated mucosal and systemic CD8+ T-cell activation post initiation of ART. These data support a loss of Th17 cells at early stages of acute HIV infection, and highlight that studies of ART initiation during early AHI should be further explored to assess the underlying mechanism of mucosal Th17 function preservation.

Background Intestinal microbial dysbiosis is evident in chronic HIV-infected individuals and may underlie inflammation that persists even during antiretroviral therapy (ART). It remains unclear, however, how early after HIV infection gut dysbiosis emerges and how it is affected by early ART. Methods Fecal microbiota were studied by 16s rDNA sequencing in 52 Thai men who have sex with men (MSM), at diagnosis of acute HIV infection (AHI), Fiebig Stages 1–5 (F1-5), and after 6 months of ART initiation, and in 7 Thai MSM HIV-uninfected controls. Dysbiotic bacterial taxa were associated with relevant inflammatory markers. Results Fecal microbiota profiling of AHI pre-ART vs HIV-uninfected controls showed a mild dysbiosis. Transition from F1-3 of acute infection was characterized by enrichment in pro-inflammatory bacteria. Lower proportions of Bacteroidetes and higher frequencies of Proteobacteria and Fusobacteria members were observed post-ART compared with pre-ART. Fusobacteria members were positively correlated with levels of soluble CD14 in AHI post-ART. Conclusions Evidence of gut dysbiosis was observed during early acute HIV infection and was partially restored upon early ART initiation. The association of dysbiotic bacterial taxa with inflammatory markers suggests that a potential relationship between altered gut microbiota and systemic inflammation may also be established during AHI.

Smallpox eradication was successful via prophylactic administration of live attenuated vaccinia virus. As a result of the discontinuation of the smallpox immunization program, many individuals are now susceptible to smallpox virus infection should it be used as a biological weapon. Presently, only individuals at high risk for exposure are required to receive smallpox vaccine, such as laboratory personnel that handle variola/vaccinia virus. This study endeavored to investigate a oneyear period of vaccinia virus-specific T cell responses using polychromatic flow cytometry and neutralizing (Nt) antibody responses using plaque reduction neutralization test (

Background: High viral load (VL) and rapid loss of CD4 + T cells are a hallmark of acute HIV infection. The association between the subsequent emergence of HIV-specific CD8 + T cells and the decrease in VL support that CD8 + T cells are crucial in the initial control of viral replication. However, little is known about the kinetics of emerging T cell responses during early acute infection (Fiebig [F] I to III) and the effect of early initiation of antiretroviral treatment (ART) on the development of HIV-specific T cells. Methods: 28 patients with acute HIV infection (11 FI/II, 17 FIII) were enrolled in the RV254/Search 010 study and immediately received ART. HIV-specific immune responses against Gag and Env peptide pools were determined in PBMC using IFN-c intracellular cytokine staining prior to ART initiation and 6 and 24 months post-ART. Results: At time of diagnosis, no HIV-specific T cell responses were detected in FI/II, while in FIII predominantly Gag-specific CD4 + responses were observed in 2/17 (12%) and CD8 + responses in 4/17 (24%) patients. Median plasma VL in FI/II was 5.5 log 10 copies/ml vs. 6.7 log 10 copies/ml in FIII (p = 0.001). At 6 and 24 months post-ART all patients had undetectable VL. However, 6 months post-ART there was no significant difference observed in the frequency of Gag-specific CD4 + and CD8 + responses between patients treated in FI/II (2/11 [18%] and 6/11 [55%], respectively), and FIII (4/17 [23%], and 8/17 [47%], respectively). The frequency of Gag-specific CD8 + T cell responses was maintained 24 months post-ART, primarily in patients that initiated ART in FIII (FI/II CD4 + : 0/11, CD8 + : 4/ 11 [36%]; FIII CD4 + : 5/17 (29%), CD8 + : 9/17 [53%] p > 0.05). Conclusions: HIV-specific T cell responses, primarily CD8 + mediated against Gag, were detected at FIII but not FI/II. However, after 6 months of ART, both groups had similar numbers of responders maybe due to viremia during the initial post-ART period or ongoing viral replication in privileged sites. OA05.05 Engineered Gag-specific T-cell Receptors RedirectPolyclonal CD8 1 T-cells to Clear HIV-1-infected CD4 1

Transgender women (TGW) are disproportionally affected by HIV infection, with a global estimated prevalence of 19.9%, often attributed to behavioral risk factors, with less known about biological factors. We evaluated potential biological risk factors for HIV acquisition in TGW at the sites of viral entry by assessing immune parameters of the neovaginal surface and gut mucosa. The neovagina in TGW, compared with the vagina in cisgender women (CW), shows distinct cell composition and may pose a more inflammatory environment, evidenced by increased CD4 + T cell activation and higher levels of soluble markers of inflammation (C-reactive protein, soluble CD30). Increased inflammation may be driven by microbiome composition, as shown by a greater abundance of Prevotella and a higher Shannon Diversity Index. In addition, we have observed higher frequency of CD4 + CCR5 + target cells and decreased DNA methylation of the CCR5 gene in the gut mucosa of TGW compared with CW and men who have sex with men, which was inversely correlated with testosterone levels. The rectal microbiome composition in TGW appears to favor a proinflammatory milieu as well as mucosal barrier disruption. Thus, it is possible that increased inflammation and higher frequencies of CCR5-expressing target cells at sites of mucosal viral entry may contribute to increased risk of HIV acquisition in TGW, with further validation in larger studies warranted.