Highly exposed but persistently seronegative individuals

The observation that HESN people remain HIV antibody-negative despite repeated exposure to HIV suggests that mechanisms exist to protect humans from HIV infection. Putative immunological and genetic associates of protection from HIV infection in HESN individuals have been identified in cohort studies of infants born to mothers with HIV infection, exposed health-care workers, and sexual partners of people with HIV infection, including sex workers in areas of high HIV prevalence. In these studies, HIV infection is excluded by the absence of HIV DNA and the inability to culture virus from peripheral blood mononuclear cells.

A number of protective mechanisms have been proposed.  Specific characteristics of the mucosal immune system that prevent HIV infection include the presence of a low inflammatory responses in the mucosa.   Low levels of activated cells may be because of poorly activated innate cells (Taborda et al., 2015) or suppressive myeloid cells and regulatory T cells (Thibodeau et al., 2017) In addition, the presence of HIV-specific immunity has been shown by the production of IgA neutralizing antibodies in mucosal secretions of HESN sex workers. (Lund et al., 2016)

Exposure to HIV in a subset of people may stimulate an effective circulating HIV-specific CD8+ T-cell response. HIV-specific CTLs have been identified in 30% of HESN men who have sex with men, heterosexual partners of people with HIV infection, infants of mothers with HIV infection, health-care workers following needlestick injuries containing HIV infected blood, and sex workers. (Cheynier et al., 1992; Clerici et al., 1992, 1994; Langlade-Demoyen et al., 1994; Rowland-Jones et al., 1995) (Ruiz-Riol et al., 2015) While HIV-specific CTLs persist for up to 34 months following HIV exposure,(Bernard et al., 1999)  repeated exposure to HIV is thought to be necessary for their maintenance. Longitudinal studies have demonstrated that HIV-specific CTLs wane during periods of reduced HIV exposure. Indeed, HIV seroconversion has been reported in sex workers during periods of reduced HIV exposure and waning HIV-specific CTLs despite previously strong HIV-specific CTL responses. (Kaul et al., 2001b)

Interestingly, CD8+ T cells of HESN people recognise CTL epitopes rarely recognised by CD8+ T cells of people with HIV infection.(Kaul et al., 2001a) Moreover, cross-clade HIV-specific CTL recognition of conserved epitopes has been demonstrated in some people. (Rowland-Jones et al., 1998) HLA restriction has been demonstrated for HESN sex workers. In a case control study, it was shown that the cells controlling infection were regulatory T cells, suggesting that the primary protection was in reducing activated target cells in the site of entry. (Pattacini et al., 2016)

Non-cytolytic HIV-specific T cell responses may also play a role in preventing HIV infection in HESN people. HIV-specific CD4+ T-cell proliferative responses occur in up to 75% of the people in the cohorts described above.(Clerici et al., 1992; Goh et al., 1999; Pinto et al., 1995)  Furthermore, increased production of beta-chemokines, which may limit HIV entry into susceptible cells, occurs in HESN people,(Furci et al., 1997; Paxton et al., 1996) as does non-cytotlytic CD8+ T cell-mediated HIV suppression.(Furci et al., 2002; Stranford et al., 1999)   The detection of HIV-specific antibody responses in HESN people is described in some but not all studies.  Local factors including serpin,(Van Raemdonck et al., 2014) trappin-2 (Iqbal et al., 2009) and innate immune responses including low PRR have been found to be present in HESN people. (Yao et al., 2014) HIV-specific IgA antibodies have been found in the vaginal fluid of HESN women participating in a microbicide trial. (Seaton et al., 2014)  Host genetics may have a role in HIV transmission but chemokine receptor polymorphisms account for only a small percentage of HESN people. In particular, CCR5 ∆32 homozygosity has been reported in up to only 3% of HESN people. (Liu et al., 1996)

Long-term non-progressors and elite controllers

Many studies have examined factors associated with slow progression to advanced HIV disease and have identified heterogenous groups designated long-term non-progressors (LTNP). These may include slow progression because of defective virus (e.g. deletion of the nef gene) or because of favourable host factors. Individuals who maintain an undetectable HIV viral load in the absence of cART (approximately 1 in 300 individuals) have been called elite controllers. (Walker, 2007)

Adaptive and innate immune responses appear to be more important than viral factors in elite controllers. The virus replicates efficiently in vitro and sequence analysis shows no demonstrable genome defects.  HLA antigens associated with a better prognosis, including HLA-B57 and -B27 are found more frequently in elite controllers. Although there is no detectable virus, elite controllers do show a gradual loss of CD4+ T cells.(Hunt et al., 2008) Elite controllers also have a lower level of immune activation and lower plasma lipopolysaccharide (LPS) levels than viraemic individuals but levels are higher than that observed in people without HIV infection. Finally, recent studies have shown that survival of central memory T cells is enhanced in elite controllers compared with people with HIV infection on cART, suggesting that elite controllers have a greater capacity to replenish HIV-infected effector memory T-cells and maintain normal T-cell numbers. The detection of DNA by the intracellular sensor cGAS is effective in conventional DC of elite controllers, which leads to type I IFN and upregulation of interferon stimulated genes (ISG).(Martin-Gayo et al., 2015)  This results in effective CD8+ CTL production. Recent work has suggested that the germinal centre and the B cell follicles may be the critical reservoir for persistent productive infection in elite controllers. (Fukazawa et al., 2015)

Post-treatment controllers

A group of patients maintaining low or undetectable HIV viral load following discontinuation of cART for primary HIV infection has been identified in the VISCONTI study.(Sáez-Cirión et al., 2013)   This group of patients does not have the genetic factors associated with control of HIV replication in elite controllers and has reduced immunological responses to HIV by antibodies and T cells.(Sáez-Cirión et al., 2013)   Preservation of central memory CD4+ T cells has been demonstrated in this group of patients.(Chéret et al., 2015)  Modelling of the HIV viral load in such patients suggests that this may represent a state where the viral reservoir is reduced below the level required to initiate further infection or to restimulate immune responses. (Conway and Perelson, 2015)  It is unclear how frequent this early control of HIV by cART may be in patients on long-term therapy after early initiation of treatment.