6 barrier by stimulating epithelial proliferation and inducing a proinﬂammatory environment by recruiting neutrophils to ﬁght microorganisms. Upon acute HIV infection follows a signiﬁcant depletion of CD4+ cells in the GALT [125, 126]. The depletion is linked to a damage of the mucosal barrier that may be due to an imbalance of Th17 cells as the massive depletion of CD4+ cells during acute HIV and SIV infection in particular includes Th17 cells [125, 126]. The damage to the mucosal barrier results in microbial translocation (MT)—a continuing leak of microbial remnants from the GI tract that enters the systemic circulation. These microbial products lead to immune activation [111, 127, 128], thereby contributing to HIV progression. The data on mucosal integrity and the inﬂuence of MT on immune activation in non-progressors are limited. One study using a rhesus macaque model has shown that spontaneous restoration of mucosal CD4+ cells upon acute SIV infection is predictive of non-progression [129]. Furthermore, EC and VC present with similar preserved numbers of CD4+ cells in rectal biopsies comparable to HIV-negative individuals, while the number in progressors is reported to be diminished [130, 131]. However, the level of lipopolysaccharide (LPS) used as a marker of MT is comparable in controllers and progressors and elevated compared to HIV-negative individuals [73], indicating that low chronic immune activation in non- progressors might have eﬀect in the long-term despite the appearance of the relatively intact mucosal barrier. Thus, present data indicate that non-progressors are distinct from progressors in several aspects of the integrity of the mucosal barrier and MT, suggesting an important mechanism for the capability of non-progressors to control immune activa- tion and HIV infection. However, to determine the causal relationship between MT and control of HIV infection prospective studies are needed. 8. HIV-Speciﬁc Immune Responses HIV-speciﬁc CD8+ and CD4+ cells and neutralizing anti- bodies are considered an important albeit most often insuf- ﬁcient element in suppressing viral replication (reviewed in [132, 133]). Some of the ﬁrst studies were made of HIV- infected patients with primary infection. Here it was shown that the level of HIV-speciﬁc CD8+ cells paralleled the eﬃciency of control of primary viremia. Also, patients who mounted strong gp160-speciﬁc CD8+ cell responses showed rapid reduction of acute plasma viremia, while viremia in patients with low virus speciﬁc CD8+ cell activity was poorly controlled [134]. Another study showed that an absent HIV- speciﬁc CD8+ cell response during primary HIV infection was associated with prolonged symptoms, persistent viremia, and low CD4+ T-cell count [135]. Furthermore, it has been shown that in vivo depletion of CD8+ cells eliminates the ability to contain SIV replication [136]. For this reason an HIV-speciﬁc CD8+ cell immune response is widely accepted as a contributor to control of viral replication and lack of progression in non-progressors, and this has been evaluated in a number of studies. Thus, it has been shown that non-progressors are able to maintain an established CD8+ cell precursor pool and present with a consistent highly AIDS Research and Treatment functional HIV-speciﬁc response, while this ability is lost in progressors [137, 138]. Also, the capacity of virus-speciﬁc CD8+ cells to proliferate in response to stimulation with HIV antigens is reported to be preserved only in non-progressors [139]. This is in agreement with ﬁndings from a prospective study of an increase in polyfunctionality in HIV-speciﬁc CD8+ cell responses from EC, and a decrease in progressors over time [140], and with ﬁndings of a stronger and broader cytokine and chemokine response following HIV-speciﬁc stimulation of PBMC from EC compared to progressors [70, 77]. In addition, it has been reported that the inhibitory immunoregulatory receptor CTLA-4 is selectively upregu- lated in HIV-speciﬁc CD4+ cells in progressors compared to non-progressors. CTLA-4 expression was also found to be positive associated with disease progression and negatively associated with the capacity of CD4+ cells to produce IL- 2 in response to viral antigen [141]. Furthermore, it has been shown that in non-progressors HIV-speciﬁc CD8+ T cells eﬃciently eliminate primary autologous HIV-infected CD4+ cells [142]. Additionally, it seems of importance if the HIV-speciﬁc cells are activated or not, as it has been shown that ECs possess lower levels of activated HIV-speciﬁc CD8+ cells and of recently divided HIV-speciﬁc CD4+ cells than progressors [70]. Based on these data an ideal HIV vaccine would induce strong HIV-speciﬁc immune responses and minimize HIV-speciﬁc immune activation. Another goal of vaccine development is induction of antibodies that neutral- ize a broad range of HIV isolates. Although antibodies can be elicited by HIV infection, those that are broadly neutralizing are undetectable in most individuals (reviewed in [143]). The level and the breadth of neutralizing antibodies are reported to correlate to viral load [144, 145], and the same or lower levels of antibodies are reported in controllers compared to progressors [144, 146]. Furthermore, one study showed that no single anti-HIV antibody speciﬁcity was a clear correlate of immunity in controllers [146]. This is consistent with neutralizing antibodies as poor contributors to non-progression. Contrary, antibodies directed against autologous Env variants are reported to be present in non-progressors [147], and eﬃcient elicitation of de novo neutralizing antibodies has been shown in SIV controllers [148]. Taken together these ﬁndings unanimously indicate that a virus-speciﬁc response by CD8+ cells is a contributing factor to non-progression, while the inﬂuence of virus- speciﬁc CD4+ cells and neutralizing antibodies is more unclear. Interestingly, similar preserved HIV-speciﬁc T-cell responses have been demonstrated in a study of controllers and LTNPs while responses were blunted in progressors [149]. This indicates that HIV-speciﬁc responses are crucial in sustaining non-progression, regardless the viral repli- cation, consequently playing a role in non-progression in controllers as well as in LTNP. However, these beneﬁcial HIV- speciﬁc responses might be a part of the explanation of why HIV is not being eradicated, even in controllers. Thus, it has recently been shown that high HIV-speciﬁc responses are associated with high levels of cell-associated HIV DNA levels in controllers [150].