Background
There is substantial variability in HIV control and disease progression among people living with HIV. Individuals can either resist infection despite repeated HIV exposure, maintain low levels of virus without antiretroviral therapy (ART) (HIV controllers), or control HIV replication to an undetectable level [elite controllers (ECs)] [
1]. Understanding the mechanisms that mediate control in these individuals may assist with developing an effective HIV vaccine or cure. However, comprehensive studies on ECs from developing countries with high disease burden are lacking, and since the introduction of universal treatment, opportunities to detect and study these unique individuals are diminishing.
Elite controllers serve as a model for determining factors associated with the protection against HIV. Clinical, immunological, host genetic and virological characteristics have been explored [
1] to determine whether elite control is due to a lack of HIV infection of CD4 target cells, replication-defective HIV variants, effective viral control by the host immune system, and/or reduced inflammation with a smaller pool of susceptible CD4 cells [
2]. Studies on ECs show that viral control is not solely due to deficient virus, but rather due to host immune responses controlling HIV replication [
1‐
3].
We investigated a longitudinal cohort of South African women who were HIV-uninfected, HIV controllers or HIV progressors. Two ECs were identified and examined in detail for clinical, immunological, host genetic and virological characteristics to understand the mechanisms responsible for viral suppression.
Discussion and conclusions
In this cohort of HIV-1 subtype-C infected South African women, the prevalence of controllers was consistent with 28 cohorts across Europe, Canada, Australia and sub-Saharan Africa [
18]. Our findings confirm that elite control is a heterogeneous phenotype with multifactorial mechanisms [
1,
6,
18]. The two ECs identified had detectable viremia within 10 months of infection, but were able to control the virus thereafter. Furthermore, they showed low levels of T-cell activation, specific cytokine T-cell responses to HIV antigens, and no evidence for reduced viral replication capacity. Host restriction factors examined here were consistent with previous studies, where ECs expressed higher levels of
p21 compared to HIV-uninfected donors, and lower levels of
CCR5 compared to HIV progressors.
Our results suggest that one mechanism responsible for elite control is a potent HIV-specific host response [
2]. For one EC, high magnitude CD8+ responses, including an immunodominant B*81:01 Gag response, shown to be beneficial [
15], likely contributed to viral control. In contrast, the other EC had detectable CD4+ responses to Gag and Pol pre-infection. We were unable to detect any evidence of virus in plasma at the ‘pre-infection’ time points, using an ultrasensitive assay. HIV-specific responses in the absence of sustained viral infection could have resulted from either abortive infection, or contained local infection foci that did not spread beyond the site of transmission, and represent ‘immune footprints’ of HIV exposure. HIV-specific responses in the absence of HIV infection have been described in HIV-exposed, but uninfected participants in the iPrEx pre-exposure prophylaxis trial, some of whom mounted high magnitude HIV-specific CD4+ and CD8+ responses [
19]. Although the iPrEx study did not determine whether these responses modified the disease course in HIV seroconvertors, the presence of certain HIV-specific responses associated with reduced HIV infection risk [
20]. It is possible that pre-infection CD4+ T cell responses in EC2 could have restricted viral replication and contributed to spontaneous control, leading to her elite controller phenotype. Additional studies would be required to investigate this further. Given the potentially high levels of HIV exposure in high incidence settings, it may be interesting to determine whether HIV-specific responses in the absence of HIV infection are more widespread, and could impact HIV infection risk or disease course.
We found heterogenous HIV neutralization activity in the two elite controllers, with neutralizing antibodies waning by year 4 in EC1, and weak responses emerging only at year 4 in EC2. It is thus unlikely that these responses contributed to HIV control. This is consistent with studies demonstrating lower neutralizing antibody titers in ECs compared to viremic patients [
21,
22]. In contrast, a recent report described multiple potent broadly neutralizing antibodies detected in an elite controller after more than 20 years of HIV infection [
23].
Upregulation of
p21 in T-cells within ECs compared to HIV-uninfected or progressors has been observed previously [
16].
p21 mediates control by blocking cyclin-dependent kinases, a group of host molecules supporting different HIV-1 replication steps [
16]. The mechanism of action for the
CCR5 gene has been well-described, i.e. elevated levels associate with loss of control by providing increased co-receptors to the virus [
17]. Our study was limited in that we did not test the full breadth of host factors that could potentially have influenced the viral control in the ECs we studied. The ligand for CCR5, CCL3, has been implicated in HIV disease progression [
24]. There is also evidence of polymorphisms in APOBEC3G and SAMHD1 contributing to control in ECs [
25,
26]. Further studies examining these and other restriction factors may shed more light on the elite controller phenotype.
In conclusion, in this case report we provide a detailed description of two elite controllers from a high burden HIV setting in South Africa, who displayed both typical and atypical features of elite control. Our results highlight the importance of studying HIV control in high incidence settings, where new insights may be gained into mechanisms of durable viral control.
Acknowledgments
We thank the CAPRISA 002 study team and all CAPRISA 002 study participants.