Elite controllers: sex differences and factors associated with loss of immune control
Richard Jefferys, TAG
Over the past few months, several interesting papers addressing elite control of HIV infection have seen publication.
The ability of elite controllers to maintain undetectable viral loads and relatively preserved CD4 T cell counts in the absence of ART has led them to be proposed as a model for a functional cure of HIV infection. But there is also evidence that many elite controllers exhibit elevated levels of inflammation compared to HIV negative counterparts, and eventually experience disease progression, leading some researchers to call this proposition into question. 
The uncertain relevance of elite control to HIV cure research is prompting studies that attempt to parse the factors distinguishing individuals who preserve elite controller status from those who ultimately progress.
In the journal eBioMedicine, Wang Zhang and colleagues explore the expression of a variety of genes and proteins in a cohort of 19 elite controllers, compared to 32 individuals with progressive HIV infection and 23 healthy HIV negative controls. 
Of particular note, nearly half the elite controllers (9) were women, allowing the researchers to compare results based on sex. The authors point out that several previous studies have reported that women tend to be overrepresented among elite controllers (e.g. see Crowell et al  and de Azevedo et al ).
A potentially important finding is that the gene expression profiles of female elite controllers were similar to HIV negative women, but there were significant differences between male elite controllers and HIV negative male controls. A potential implication is that women will be more likely to maintain elite controller status over time compared to men – this possibility will need to be investigated further.
Among the differences observed in elite controllers compared to individuals with progressive HIV infection were downregulation of the genes for CXCR6 and SIGLEC1. The authors explain that these differences could be associated with decreased susceptibility of CD4 T cells for HIV entry and reduced cell-to-cell virus transmission mediated by myeloid cells.
Levels of the chemokine CCL4 (MIP-1β) were found to be higher among elite controllers versus progressors, consistent with a previous study.  Conversely, levels of the inhibitory immune cell receptor PD-1 (and its ligand PD1-L2) were significantly lower, echoing another recent paper reporting lower levels of multiple inhibitory receptors in elite controllers. 
has published an analysis by José Benito and colleagues that looks at possible contributors to loss of elite control. 
The researchers evaluated 36 elite controllers followed for approximately a decade on average, comparing multiple immunological parameters between those with stable CD4 T cell counts (n=22) and those exhibiting significant CD4 T cell decline during the follow up period (n=14). Interestingly, women made up 67% of the former group but only 31% of the latter, a statistically significant difference (p=0.04). The authors don’t offer any comment on this apparent overrepresentation of women in the group of elite controllers with stable CD4 T counts.
Many immunological variables were found to differ between elite controllers and HIV-negative healthy controls, as well as between stable elite controllers and those experiencing CD4 T cell declines. Distinctions between elite controllers and HIV negative healthy controls included lower levels of several T cell subsets: naïve, recent thymic emigrant, stem cell memory, and regulatory. Expression of the T cell costimulatory receptor CD28 was lower, whereas CD95 – involved in apoptotic cell death – was increased.
Comparisons between the stable elite controllers and progressors revealed that the latter group had lower levels of naive and recent thymic emigrant CD8 T cells, as well as higher levels of CD8 T cells with effector memory and senescent phenotypes. The finding suggests that CD8 T cells may have been differentiating at a higher rate in this group – in other words, naive CD8 T cells were more frequently becoming activated and transitioning into memory cells (perhaps reflective of a more strenuous battle to keep HIV contained). The progressor group also showed increased expression levels of PD-1 in both total CD4 T cells and the central memory CD4 T cell subset.
In a separate study published in the Journal of Virology earlier this month, María Pernas and colleagues conducted a retrospective, longitudinal analysis of factors contributing to loss of viral load suppression in a cohort of elite controllers. 
A total of 31 elite controllers were included, defined based on having viral load below detectable levels (50 copies/mL) on three consecutive measures over a year of follow up.
Fourteen of these individuals subsequently experienced increases in viral load (two consecutive measures above the detection limit within a year), and were classified as transient controllers. The remaining 17 maintained undetectable viral loads and were classified as persistent controllers. Sex differences were not apparent in this study, with women making up 43% of the former group and 41% of the latter. The only significant differences were for time since diagnosis (averaging 8 years and 18 years, respectively) and sexual transmission as mode of HIV acquisition (71% vs. 35%).
The availability of samples prior to the viral load increases in the transient controller group allowed several factors associated with the loss of HIV suppression to be identified. CD8 T cells targeting the HIV Gag protein were found to be significantly less polyfunctional (assessed based on production of the cytokines IFN-γ, TNF-α and IL-2) and displayed a more activated phenotype a year prior to viral load becoming detectable. HIV genetic diversity within the env
gene was also significantly higher, with a similar trend observed for the gag
gene. In contrast, persistent controllers showed little or no evidence of ongoing viral evolution.
Inflammatory biomarkers were elevated in the transient controllers. and an analysis of 70 different cytokines and chemokines in plasma samples revealed that increased levels of RANTES and Platelet Derived Growth Factor (PDGF) AA were the best predictors of subsequent loss of elite controller status. RANTES in particular showed a strong association, being an average of four-fold higher in transient controllers.
In discussing their results, the authors emphasise the importance of focusing on examples of strict, persistent control of HIV if the goal is to identify “the right model of functional remission.” They also suggest that factors strongly predictive of future viral load rebound—such as RANTES levels—might have the potential to help discriminate elite controllers likely to benefit from ART from those who may not require it.
Similar points are made in a commentary in EBioMedicine
by Laura Tarancon-Diez and colleagues.  The commentary accompanies a paper describing an elite controller who has maintained extremely low levels of HIV RNA and HIV DNA for a decade, without fully seroconverting on the Western Blot antibody assay.  Evidence of polyfunctional HIV-specific CD8 T cell responses and strong antibody-mediated cellular cytotoxicity (ADCC) by natural killer cells is reported. The individual acquired HIV from a partner who was not able to control the same CRF02_AG virus variant. Neither partner possesses known favorable HLA alleles although both are heterozygous for the CCR5Δ32 mutation. 
The commentary also cites work published last year from the French CODEX cohort, which described a subset of HIV controllers in whom viral load had never been detectable using routine assays during an average of 18 years of follow up. In a comparison with controllers who had experienced viral load blips, T cell counts were reported to be stable (as opposed to progressively declining), and this was accompanied by lower T cell activation and HIV DNA measurements. This study also showed a trend toward an overrepresentation of women in the persistently undetectable group (34 out of 52, 65%) versus the viral load blips group (90 out of 178, 51%, p=0.06).
Tarancon-Diez and colleagues advocate concentrating on “this very scarce proportion of individuals that are able to persistently control the virus” in order to inform the design of cure strategies aiming to induce long-term remission in the absence of ongoing ART.
Whether there might be particular features of the immune response (or other factors) in women that increase the likelihood of persistent elite control needs to be elucidated. Ongoing work is investigating possible differences related to HIV persistence in women receiving ART, with Eileen Scully presenting the latest findings from her research as a poster at the CROI 2018 conference. 
Scully has uncovered a number of significant sex-based associations, including higher expression of several antiviral genes.
As Zhang and colleagues argue in the closing section of their EBioMedicine paper: “Despite extensive data on the male and female difference on disease outcome, research does not sufficiently take gender into account. Altogether, our study showed that it would be important to carefully consider gender in cohort design for future transcriptomic and intervention studies on HIV-1 patients.”
Jefferys R. Elite controllers: sex differences and factors associated with loss of immune control. (14 March 2018).
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- What is the most important for elite control: genetic background of patient, genetic background of partner, both or neither? Description of complete natural history within a couple of MSM. eBioMedicine (2018). (27)51–60. doi: 10.1016/j.ebiom.2017.12.003.
- Scully P. Sex-based differences in transcriptomic profiles and HIV reservoir correlates. 25th CROI, 4-7 March 2018, Boston.
http://www.croiconference.org/sessions/sex-based-differences-transcriptomic-profiles-and-hiv-reservoir-correlates (abstract and poster)