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. Author manuscript; available in PMC: 2022 Sep 1.
Published in final edited form as: Curr Opin HIV AIDS. 2021 Sep 1;16(5):243–248. doi: 10.1097/COH.0000000000000693

Immunological effector mechanisms in HIV-1 elite controllers

Ciputra Adijaya Hartana 1, Xu G Yu 1,2,*
PMCID: PMC8373669  NIHMSID: NIHMS1722740  PMID: 34270465

Abstract

Purpose of review

HIV-1 elite controllers encompass small populations of people infected with HIV-1 who can spontaneously control plasma viral loads below the limit of detection, in the absence of antiretroviral treatment. Antiviral immune responses are likely to contribute to such an impressive HIV-1 disease outcome. In this review, we discuss recent novel findings regarding antiviral innate and adaptive immune responses in elite controllers.

Recent findings

Elite controllers maintain a pool of infected cells in which intact HIV-1 proviruses are more frequently integrated in non-coding regions of the host genome, likely conferring a state of deep latency. This atypical viral reservoir configuration is best explained by potent antiviral immune responses that can successfully eliminate virally infected cells in which proviruses are integrated in permissive chromatin. However, identifying the specific type and nature of this immune selection pressure represents a formidable challenge. Recent studies continue to support the role of HIV-1-specific CD8+ T cells as the main driver of elite immune control of HIV-1, however, increasing evidence suggests that their role is complemented by a fine-tuned interplay with innate immune cell subsets. Therefore, the combination of different immune effector mechanisms may shape antiviral immunity in elite controllers.

Summary

Understanding the complex immune mechanisms responsible for natural, drug-free HIV-1 control represents a premier avenue to find and develop interventions for a cure of HIV-1 infection. Future single-cell assays designed to uncover the full genetic, epigenetic, transcriptional and functional complexity of antiviral immune responses in elite controllers may allow us to define correlates of antiviral immune protection in greater detail.

Keywords: Elite controllers, HIV infections, immune response

Introduction: Elite controllers

The use of highly active antiretroviral therapy (ART) has dramatically changed the disease progression of HIV-1 infection from a death sentence to a manageable chronic disease. Viral replication in HIV-1 infected individuals can be optimally controlled by strict adherence to ART, and therefore prevents the progression to acquired immune deficiency syndrome (AIDS) (1). However, weak adherence to ART, limitation in access to the medication, and the emergence of drug resistance remain the central problems to end the epidemic through ART alone (2). Therefore, innovative strategies to understand not only the basis of immune control, but also the failure of such control are currently needed for the discovery of novel immunological targets and the development of preventative and therapeutic interventions.

Notably, effective control of HIV-1 infection and disease progression can occur spontaneously. Approximately 1 in 300 HIV-1 infected individuals called “elite controllers”, are capable of maintaining their viral loads below detection levels for an extended period of time, in the absence of antiretroviral therapy (3). A recent study demonstrates that in elite controllers, genome-intact HIV-1 proviral sequences are integrated in repressive chromosomal regions, presumably conferring a state of deep latency (4). This may suggest that immune-mediated selection mechanisms in elite controllers are able to drive such a highly distinct viral reservoir configuration through preferential elimination of proviruses more susceptible to reactivation signals. Additionally, a limited proviral evolution over time is reported in elite controllers (5–8). The extraordinary ability of elite controllers to control HIV-1 replication provides an exquisite opportunity to study the dynamics of immune responses in restricting viral turnover in these individuals. In this article, we will outline recent novel discoveries of immunological effector mechanisms to control HIV-1 replication in elite controllers.

Immunological effector mechanisms by adaptive immune cells

We outline known and recent findings regarding immune effector mechanisms by adaptive immune system in elite controllers below.

CD8+ T cells

HIV-1-specific CD8+ T cells arguably represent the main mediators of durable viral suppression in HIV-1 elite controllers. Early investigations supporting the role of CD8+ T cells in HIV-1 control included genome-wide association studies of thousands of individuals, which established that polymorphisms within the HLA class I binding pocket are correlated to natural HIV-1 control (9). These variations of amino acid positions define specific HLA class I alleles, such as HLA-B*57, HLA-B*52 and HLA-B*27, which allow presentation of HIV-1 viral peptides on infected cells to be recognized by the T cell receptors of HIV-1-specific CD8+ T cells (9, 10). However, the genetic associations in the HLA class I gene locus account for less than 25% of the observed variance in host immune control (9). In addition, a recent topological network analysis suggested that HIV-1-specific CD8+ T cells from controllers target highly networked epitopes, regardless of the presence of the protective HLA alleles (11). This indicates that the three-dimensional network architecture of viral epitopes may influence natural viral suppression in HIV-1 controllers, independent from the restricting HLA class I allele.

Three recent studies provided evidence that CD8+ T cell functions are enhanced in elite controllers, and complemented prior observations in this regard (12–14). An in vitro study demonstrated that HIV-1 specific CD8+ T cells from elite controllers can reduce HIV-1 replication in infected CD4+ T cells by 60-80%; moreover, this suppression was further amplified after administration of exogenous IFN-α, suggesting a connection between adaptive CD8+ T cells and innate immune modulators (15). Extending these findings, a recent report suggested that HIV-1 specific CD8+ T cells from elite controllers are capable of recognizing resting HIV-1-infected CD4+ T cells and to kill such cells in the absence of viral reactivation (16); this observation may explain why cellular immune responses in elite controllers can effectively reduce proviral reservoirs. Reduced frequencies of proviral HIV-1 DNA in elite controllers has indeed been observed in multiple prior studies (4, 17). Furthermore, CD8+ T cells from elite controllers might have a higher cell-intrinsic activation of the canonical Wnt signaling pathway, which mediates non-cytolytic inhibition of HIV-1 transcription in infected cells, and may restore CD4+ T cell count (18).

In order to control viral replication, CD8+ T cells must effectively traffic and localize to the anatomical sites where HIV-1 persists, such as the mucosal and lymphoid tissues. Viral control in elite controllers is associated with polyfunctional HIV-1-specific memory CD8+ T cells from lymph nodes (LNs) of elite controllers, which actively suppress viral replication, although displaying weak cytolytic activities (lower perforin and granzyme B expression compared to chronic progressors) (19). These LN CD8+ T cells from elite controllers also have a higher expression of the B cell follicle homing marker CXCR5 and a lower expression of inhibitory receptors, such as TIGIT, LAG3 and CD244, compared to chronic progressors (19). Moreover, HIV-1-specific memory CD8+ T cells in the lymphoid tissues of elite controllers frequently resemble tissue-resident memory T cells (TRM), with skewed clonotypes and higher effector/cytolytic gene expression, suggesting that these cells are the frontline of defense in lymphoid tissues of elite controllers (20).

Immunometabolic parameters may also contribute to persistent spontaneous control of HIV-1 replication in elite controllers. Persistent elite controllers, who can consistently maintain their undetectable viral loads, have fewer plasma metabolomes involved in glycolysis, the Krebs cycle or amino acid catabolism compared to transient elite controllers, who have lost their spontaneous viral control; notably; these elevated plasma metabolic markers correspond to a limited polyfunctionality of HIV-1-specific CD8+ T cells in controllers who eventually display signs of viral rebound (21). On the contrary, lipidomic measurements suggested that seven plasma lipids are found to be higher in elite controllers, and associated with more polyfunctional HIV-1-specific CD8+ T cells in persistent elite controllers (21). These studies resonate with a single-cell gene expression analysis of HIV-1 specific CD8+ T cells from elite controllers and ART-treated HIV-1-positive individuals (22). In this study, HIV-1-specific CD8+ T cells from elite controllers are more poised towards a central memory phenotype and upregulate genes involved in effector functions and cell survival, whereas HIV-specific CD8+ T cells from ART-treated subjects have a higher expression of genes linked to mTORC1 activation and glycolysis (22). Consequently, CD8+ T cells from ART-treated individuals strongly depend on glycolysis and high glucose uptake, whereas elite controller CD8+ T cells have a metabolic plasticity with a higher uptake of fatty acids, which are associated with a higher effector gene expression (22).

Taken together, these novel studies continue to support CD8+ T cells as the leading actor in spontaneous control of HIV-1 replication in elite controllers. However, recent evidence has indicated that the protective roles of CD8+ T cells is not only limited to the higher frequency of protective alleles. Instead, effective CD8+ T cell responses in viral control may be achieved through better effector functions, localization and immunometabolic activities in elite controllers.

CD4+ T cells

CD4+ T cells may also be involved in shaping the natural viral control in elite controllers, however, studies involving CD4+ T cell effector mechanism are scarce. One report suggested CD4+ T cells from elite controllers to highly express sterile α motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1) which can inhibit reverse transcription of HIV-1 (23). This expression of SAMHD1 may be associated with low immune activation levels in elite controllers (23). In addition, HIV-1-specific CD4+ T cells from elite controllers might have more dominant gene expression signatures associated with Th1, Th17 and Th22 polarization, whereas a T follicular helper (TFH)-like gene profile is seen in HIV-1 viremic individuals, suggesting that specific alterations in CD4+ T cell polarization may contribute to antiviral immune defense in CD4+ T cells from elite controllers (24). One alternative transcriptional profiling study found that resting memory CD4+ T cells from elite controllers are enriched in various pathways influencing activation, differentiation and cytotoxicity of CD4+ T cells (25); however, functional data will be needed to validate this study. Additionally, a small frequency of HIV-1-specific CD57+ CD4+ T cells, characterized by granzyme B and perforin expression, is present in elite controllers (26), suggesting that CD4+ T cells may play a direct role in killing virally-infected cells in elite controllers, and at the same time, complement the cytotoxic activities of HIV-1-specific CD8+ T cells. This notion is further supported by a small clinical trial involving an adoptive lymphocyte transfer from an elite controller to an HIV-1 chronic progressor, which demonstrated that three days after adoptive transfer, a transient decrease of viral load was seen, along with peak frequencies of Ki67+ granzyme B+ perforin+ CD8+ T cells in the recipient (27). Notably, a peak frequency of Ki67+ CD4+ T cells was also observed three days after adoptive transfer, but these cells returned to the baseline level earlier than CD8+ T cells (27). Altogether, these results suggest that CD4+ T cells from elite controllers may have effector functions to support CD8+ T cell responses; however, more dedicated studies are needed to validate such CD4+ T cell functions.

Humoral immune responses

The role of humoral immune responses in natural control of HIV-1 infection has been increasingly appreciated. Even though elite controllers generally have lower neutralizing antibody titers compared to viremic HIV-1-infected individuals (28, 29), antibodies with broad cross-neutralization capacity (broadly neutralizing antibodies/bNAbs) against diverse HIV-1 strains could be cloned from HIV-1-specific memory B cells from a small number of elite controllers (30). This indicates that elite controllers are capable to produce potent anti-HIV-1 antibodies. Additionally, a higher frequency of memory B cells are preserved in elite controllers compared to ART-treated individuals (31). The memory B cell pool seems to be maintained by HIV-1-specific CD4+ TFH cells, which are higher in elite controllers than in ART-treated individuals (30, 32).

One important mechanism of viral control is antigen-dependent cellular cytotoxicity (ADCC). This mechanism involves HIV-1 Env recognition on the surface of HIV-1-infected cells by antibodies, which in turn would mediate the ADCC process (30). Using a flow cytometry-based approach to measure antibodies recognizing gp120-expressing cells from the plasma of HIV-1-infected individuals, one study showed that the plasma from elite controllers has a higher level of these antibodies than the plasma from ART-treated individuals (33). Consequently, antibody dependent functions, which include cellular phagocytosis, cellular cytotoxicity and trogocytosis may be improved in elite controllers compared to ART-treated individuals, suggesting a contribution of this mechanism in spontaneous viral control (34). Additionally, anti-membrane proximal external region (MPER) of the HIV-1 gp41 fusion protein neutralizing antibody, namely LN01, was isolated from the germinal center B cells from the lymph nodes of an elite controller (35). This antibody is potently neutralizing and broadly cross-reactive across a range of viral quasispecies (35), adding another potential way of viral restriction in elite controllers.

The modifications in the structure of HIV-1 Env protein expressed on the surface of infected cells may also contribute to the recognition and neutralization by neutralizing antibodies. A study discovered an elongation in the Env V1 domain in one elite controller, which may attenuate the infectivity and fitness of the virus, without conferring resistance to broadly neutralizing antibodies (36). This is further supported by another study with a similar finding, in which two additional cysteine residues were seen in the elongated V1 region of HIV-1 Env protein of an elite controller (37). As a result, bNAbs displayed higher binding and neutralization capacities towards this modified Env protein (37).

Overall, an increasing body of evidence suggests that humoral immune responses can be a contributing factor to natural viral control in elite controllers. In particular, humoral immune protection in elite controllers seems to be characterized by a combination of a higher memory B cell frequency, better neutralization titers and improved breadth of bNAbs. However, these mechanisms do not occur universally in all elite controllers; their true contribution to an elite controller phenotype will require additional investigations.

Immunological effector mechanisms by innate immune cells

Most studies have described HIV-1 immune control by virus specific T cell responses (38), with a higher T cell polyfunctionality (19, 39) correlating to a better viral control in HIV-1 disease progression. However, in recent years, innate immune cells have also been related to natural control of HIV-1. Moreover, the emerging concept of trained innate immunity further expands the possibility that viral control may be achieved through memory-like behavior of innate cells (40–43). Here, we will describe some novel discoveries of disease control by innate immune cells in elite controllers.

NK cells

As innate effector cells, NK cells have similar functional features with their evolutionary cousins, CD8+ T cells, as seen by the rapid dynamic changes in their chromatin architecture during the early phase of infection (44). Around 30% of chromatin regions harboring immune effector genes, such as Prf1, maintain increased accessibility in NK cells, indicating that epigenetic programming in NK cells may imitate T cells during their transition from naïve to memory cells (45).

In HIV-1 infection, a preliminary study indicates that there is no synergistic nor antagonistic effects between NK cells and CD8+ T cells from HLA-B*57 elite controllers in restricting HIV-1-infected cells using in vitro co-culture assays; instead, viral control by one cell subset seems independent of the other (46). Furthermore, in HIV-1 elite controllers and supercontrollers (HIV-1 elite controllers that are able to spontaneously control Hepatitis C virus (HCV)), the frequency of cytotoxic CD56dim NK cells are almost two times higher compared to HIV-1 non-controllers (47). The CD56dim NK cells are also shown to express lower levels of exhaustion markers LAG3, TIGIT and CXCR6 in elite controllers (47). Notably, high-throughput mass cytometry suggested that a cluster of cells with CD11b+ CD57− CD161+ Siglec-7+ phenotypes within the CD56dim CD16+ NK cell subset is more abundant in elite controllers (48). This cell cluster seems to be more functional, showing a better IFN-γ production and cytotoxic degranulation as measured by CD107a surface expression (48). Therefore, these studies suggest that NK cells in elite controllers consist of cell subsets with better effector and cytotoxic functions, which may be comparable to the effector mechanism mediated by CD8+ T cells. Notably, liver and peripheral blood CD49a+ CD16− NK cells are primed to have an antigen specific cytotoxicity and display signs of distinct epigenetic and transcriptomic profiles, reminiscing of memory CD8+ T cells, which may suggest “trained” NK cell responses (49). Clearly, phenotypic, transcriptional and epigenetic characteristics of NK cell subsets in elite controllers require more investigation in future studies.

Dendritic cells

Over the past few years, the role of dendritic cells in the viral control of HIV-1 elite controllers has been increasingly appreciated. The frequencies of plasmacytoid dendritic cells (pDCs) are higher in elite controllers compared to non-controllers, with a positive correlation to the frequencies of polyfunctional HIV-1-or HCV-specific CD4+ and CD8+ T cells (47). Notably, the frequencies of pDCs expressing the immunomodulatory receptors LILRA4 and LILRB4 are negatively correlated with HIV-1 viral loads (50). In addition, some studies showed that pDCs produce type I IFN to act against virally infected cells (51–53). Although, these studies were done on ART-treated individuals, one can argue that IFN responses could contribute to the elimination of proviral reservoirs that are permissive to reactivation in elite controllers.

Furthermore, myeloid dendritic cells (mDCs) from elite controllers show increased expressions of CD64 and PD-L1 following HIV-1 infection in vitro, and these CD64hi PD-L1hi mDCs elicit stronger allogenic CD4+ and CD8+ T cell proliferations, as well as a potent HIV-1-specific CD8+ T cell activation, as seen by IFN-γ production and degranulation (54). This study suggests an important contribution of mDCs from elite controllers to viral control, likely through modulation and fine-tuning of antiviral cellular immune responses. Additionally, recent data demonstrated that mDCs isolated from HIV-1 controllers with superior neutralizing breadth against HIV-1 are capable to facilitate naïve CD4+ T cell differentiation into CXCR5+ PD-L1+ T follicular helper (TFH)-like cells, which likely causes the numerical increase of TFH/Th1 CD4+ T cells in these HIV-1 controllers (55). Moreover, mDCs from elite controllers appear to have enhanced immune activation (50) and metabolic functions, which is associated with distinct epigenetic profiles regulated by long noncoding RNA, resulting in a better antigen presentation (56). This study supports that trained innate immune cells, previously described in a variety of disease contexts (41), may be active in elite controllers and contribute to viral control in this specific population.

Conclusion

Increasing pieces of evidence suggest that immune-mediated effector responses may mediate selection pressure on HIV-1-infected cells in elite controllers, leading to a proviral integration site landscape that is atypically biased to gene deserts of the host genome, conferring deep viral latency. The combination of both innate and adaptive arms of immune responses may be responsible for such potent effector responses in elite controllers. Future investigations of effector immune responses from elite controllers may provide important clues for finding novel immunological targets for spontaneous control of HIV-1 infection.

Key points.

  1. In elite controllers, genome-intact HIV-1 proviral sequences are integrated in repressive chromosomal regions, conferring a deep latency, which may suggest a selection pressure by immune-mediated effector mechanisms.

  2. CD8+ T cell-mediated protection in elite controllers is not only limited to the higher frequency of protective alleles, but also through better effector functions, localization and immunometabolic activities.

  3. CD4+ T cells from elite controllers may have effector functions to support CD8+ T cell responses.

  4. Humoral immune responses contribute to viral control in elite controllers through a combination of a higher memory B cell frequency, better neutralization titers and improved breadth of bNAbs.

  5. Innate NK cells and dendritic cells may be trained and more active in elite controllers, which contribute to viral control.

Acknowledgements

X.G.Y. is supported by NIH grants HL134539, AI116228, AI078799, DA047034, AI155171, AI150396 and the Bill and Melinda Gates Foundation (INV-002703) and is an Associated Member of the BEAT-HIV Martin Delaney Collaboratory (UM1 AI126620).

Footnotes

Declaration of Interests

The authors declare no competing interests.

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