a Mutation frequency in the protein sequence of plasma SIV Env variants isolated from SIVsab92018ivTF-infected AGMs and SIVmac251-infected RMs was quantified as the percent of Env variants showing a different amino acid compared to that of the challenge viral Env from the total number of variants. is dominated by non-neutralizing antibodies targeting Env gp41. In contrast, natural primate SIV hosts, such as African green monkeys (AGMs), develop a Rabbit Polyclonal to ERGI3 predominant Env gp120-specific antibody response to SIV infection. However, the fine-epitope specificity and function of SIV Env-specific plasma IgG, and their potential role on autologous virus co-evolution in SIV-infected AGMs and RMs remain unclear. Results Unlike the dominant linear gp41-specific IgG responses in RMs, SIV-infected AGMs demonstrated a unique linear variable loop 2 (V2)-specific plasma IgG response that arose concurrently with high gp120-directed antibody-dependent cellular cytotoxicity (ADCC) activity, and SIVsab-infected cell binding responses during acute infection. Moreover, SIV variants isolated from SIV-infected AGMs exhibited high amino acid mutation frequencies within the Env V1V2 loop compared to those of RMs. Notably, the linear V2-specific IgG epitope in AGMs overlaps with an analogous region of the HIV V2 loop containing the K169 mutation epitope identified in breakthrough viruses from RV144 vaccinees. Conclusion Vaccine-elicited Env V2-specific IgG responses have been proposed as an immune correlate of reduced risk in HIV-1/SIV acquisition in humans and RMs. Yet the pathways to elicit these potentially-protective V2-specific IgG responses remain unclear. In this study, we demonstrate that SIV-infected AGMs, which are the natural hosts of SIV, exhibited high plasma linear V2-specific IgG binding responses that arose concurrently with SIV Env gp120-directed ADCC-mediating, and SIV-infected cell plasma IgG binding responses during acute SIV infection, which were not present in Defactinib acutely SIV-infected RMs. The linear V2-specific antibody response in AGMs targets an overlapping epitope of the proposed site of vaccine-induced Defactinib immune pressure defined in the moderately protective RV144 HIV-1 vaccine trial. Identifying host factors that control the early elicitation of Env V2-specific IgG and ADCC antibody responses in these natural SIV hosts could inform vaccination strategies aimed at rapidly inducing potentially-protective HIV-1 Env-specific responses in humans. Electronic supplementary material The online version of this article (10.1186/s12977-018-0406-5) contains supplementary material, which is available to authorized users. Keywords: SIV, Linear peptide antibody responses, Natural SIV host, African green monkey, Rhesus monkey, Antibody response, ADCC, Envelope, gp120, gp41 Background The HIV-1 Env glycoprotein contains multiple vulnerable epitopes targeted by potent broad neutralizing antibodies (bNAbs) [1]. However, the elicitation of HIV gp120-specific bNAbs by current Env vaccination strategies is not yet feasible [2, 3]. Thus, HIV vaccine candidates currently in clinical testing focus on the elicitation of antibody specificities and functions identified as potential immune correlates of reduced infection risk in human and non-human primate vaccine efficacy studies. Immune analyses from the HVTN 505 phase IIb vaccine trial, which utilized an HIV Env gp140 protein boost immunogen and failed to show efficacy, demonstrated that the vaccine-elicited humoral responses primarily targeted HIV Env gp41 without identifiable antiviral functions [4]. Similarly, in the setting of HIV-1 infection, the initial antibody response against HIV Env is also dominated by Env gp41-specific IgG responses that are ineffective at controlling viremia [5, 6]. Interestingly, in the moderately-efficacious RV144 HIV-1 Env vaccine efficacy trial, Env-specific IgG responses targeting the variable loop 1 and 2 (V1V2) were found to be associated with reduced HIV acquisition risk [7]. The following sieve analysis of the breakthrough virus variants localized the site of vaccine-induced immune pressure to two amino acid residue positions within V2 loop [8C10]. Moreover, the V2 epitope that was associated with immune escape in RV144 vaccinees spans the region capable of engaging the gut-homing integrin receptor 47, which has been implicated in the trafficking of immune cells to the gut associated lymphoid tissue, and the enhancement of cell-to-cell HIV transmission [11C13]. Furthermore, the HIV Env V2-specific IgG responses in RV144 vaccinees mediated ADCC activity [14, 15]. Defactinib Notably, V2-specific IgG responses were also associated with a reduced risk of SIVmac251 acquisition in RMs that received a similar vaccine regimen to that in the RV144 HIV-1 trial [16]. While these types of V2-specific IgG responses are a major clinical endpoint of HIV vaccination, our understanding of factors that control the elicitation of V2-specific IgG responses and ADCC function by existing vaccination strategies remains limited [3, 17]. Previous studies have investigated the proportion of SIV Env-specific IgG responses in the setting of infection in natural and non-natural SIV Defactinib hosts. Antibody responses in acute SIV infection of RMsa non-natural SIV host species and model of AIDS pathogenesispredominantly target the SIV Env.