Antiretroviral therapy (ART) has significantly extended the life expectancy of people with HIV (PWH). However, as this population ages, they face increased risk of social isolation and loneliness (SIL), driven by stigma, discrimination, and shrinking social networks. SIL is a major public health issue, closely linked to mental health conditions, reduced adherence to treatment, and lower health-related quality of life (HRQoL). This review examines the prevalence, risk factors, health impacts, and interventions related to SIL, highlighting its critical importance for improving HRQoL in PWH. SIL is common among PWH and strongly associated with HIV-related stigma, depression, anxiety, and systemic inflammation. These factors accelerate aging and contribute to chronic conditions while undermining ART outcomes. Recent research supports the effectiveness of interventions like psychological therapies and social prescribing in reducing SIL and improving HRQoL. However, progress is limited by the lack of standardized tools to assessment SIL, which hampers consistent research and the development of targeted solutions. Addressing SIL is essential to advancing holistic and person-centered HIV care. Integrating SIL evaluation into routine clinical practice, creating standardized assessment tools, and implementing targeted interventions can improve HRQoL and reduce health burdens, particularly as the aging PWH population grows.

Natural killer (NK) cells are integral components of the innate immune system, serving a vital function in eliminating virally infected cells. This review highlights the significance of CXCR5+ NK cells in the context of chronic HIV/SIV infection and viral control. Controlled HIV/SHIV infection results in a substantial increase in the population of CXCR5+ NK cells within the B-cell follicles of secondary lymphoid organs (SLOs). These CXCR5+ NK cells display enhanced functional characteristics, including elevated expression of activation markers and increased cytokine production, which are essential for effective viral control. These follicular NK cells are shown to be enriched in IL-15 signaling, and CXCR5 NK cells are negatively associated with viral burden during chronic HIV and SHIV infection. The distinct phenotypic and functional attributes of CXCR5+ NK cells, particularly in the lymphoid tissues of individuals living with HIV, emphasize their critical contribution to the anti-HIV-1 immune response. A comprehensive understanding of the mechanisms and roles of CXCR5+ NK cells may present novel therapeutic strategies aimed at enhancing NK-mediated viral control.

Despite decades of insights about the role of natural killer (NK) cells in HIV infection, their persistent dysregulation despite antiretroviral therapy (ART) and its pathological consequences have been incompletely delineated. In this review, we highlight recent findings on the immunophenotypic and functional alterations of NK cells during virally suppressed HIV infection and explore their potential impact on promoting non-AIDS related comorbidities among people living with HIV (PLWH). Of note are the apparent persistent activated profiles of NK cells and pathophysiological events such as endoplasmic reticulum (ER) stress in potentially driving NK cell derived inflammation and tissue destruction. Additionally, recent interest in trained immunity is discussed as a potential mediator of ongoing NK cell dysregulation, contributing to comorbidities such as cardiovascular disease and neurocognitive disorders, both with an inflammatory etiology. Clinical and mechanistic evidence suggests persistent activation and dysregulation of the innate immune system are major drivers of non-AIDS comorbidities during virally suppressed HIV infection. Delineating the mechanistic role of specific components of innate immunity such as NK cells in inducing these pathologies will lead to the identification of novel therapeutic/prophylactic strategies to improve the overall health of PLWH.

This review highlights the role of monocytes in the pathogenesis of HIV-1 infection, focusing on their involvement in the inflammatory response and their function as viral targets and long-term reservoirs. Monocytes have been categorized into three subsets: classical, intermediate, and nonclassical, each with distinct functional characteristics. Advances in genetic sequencing technologies have enabled a more in-depth exploration of the phenotypic and functional variations among these subsets, particularly in the context of HIV. These findings underscore their role as crucial components of the immune response and as reservoirs for the virus. Previous studies on the role of monocytes have demonstrated their contribution to persistent infection and chronic immune activation, especially in adults living with HIV. The lessons learned from these studies should now be harnessed to design studies focused on newborns and children with vertically acquired HIV.

Women are underrepresented in HIV infection and prevention research despite making up half of people living with HIV. The female genital tract (FGT) serves as a primary site of HIV acquisition, but gaps in knowledge remain regarding protective innate immune mechanisms. Innate lymphoid cells are tissue-resident cells involved in mucosal barrier maintenance and protection, and innate lymphoid cells (ILCs) are altered during chronic HIV infection. However, ILCs role in mucosal HIV pathogenesis is unclear and they are poorly characterized in the FGT. Human ILCs differ from their mouse counterparts and plastically adjust to their tissue of residency. Human ILC characterization is difficult due to tissue-specific adaptations and transition between subsets. While evidence for ILC involvement in antiviral activity and barrier maintenance is provided in mouse models, human ILC role in mucosal immunity remain understudied, particularly in the FGT. In chronic HIV/simian immunodeficiency virus (SIV) infection, ILCs are altered in a tissue-specific manner, and SIV models indicate potential for antiviral responses. ILCs are tissue-resident plastic cells that provide barrier protection at mucosal surfaces and display antiviral capacity. Considering that HIV is primarily transmitted through mucosal exposure, more research is needed to understand ILC contribution to HIV pathogenesis in human mucosal surfaces relevant for HIV acquisition.

Like elephants (and T cells), accumulating evidence suggest natural killer (NK) cells never forget. The description of adaptive or memory NK cells, which can be induced by HIV/SIV infections and vaccines and associated with protective effects in persons with HIV (PWH), has dramatically increased the interest in leveraging NK cells to prevent HIV infection or suppress HIV reservoirs. However, harnessing their full antiviral potential has been hindered by an incomplete understanding of mechanisms underlying adaptive NK cell development and infected cell recognition. Herein, we outline the main discoveries around the adaptive functions of NK cells, with a focus on their involvement in HIV infection. NK cells with diverse adaptive capabilities, including antigen-specific memory, cytokine-induced and CMV-driven adaptive subsets, likely all play a role in HIV infection. Importantly, true antigen-specific memory NK cells have been identified that mediate recall responses against multiple infectious agents such as HIV, influenza, and SARS-CoV-2. The NKG2C receptor is pivotal for certain adaptive NK cell subsets, as it marks a population with enhanced antibody-dependent functions and has been described as the main receptor mediating antigen-specific responses via recognition of viral peptides presented by HLA-E. Antiviral functions of adaptive/memory NK cells have tremendous, but as of yet, untapped potential to be harnessed for vaccine design, curative, or other therapeutic interventions against HIV.

Typically, both HIV-infected humans and simian immunodeficiency virus (SIV)-infected Asian nonhuman primates (NHPs) eventually progress to AIDS, while African NHPs that are natural hosts of SIV do not, in spite of life-long, high levels of viral replication. Lack of disease progression in African NHPs is not due to some adaptation by the virus, but rather to host adaptations to the virus. Central to these adaptations is maintenance of the gut integrity during acute viral replication and inflammation, which allows natural hosts to avoid the chronic inflammation characteristic to pathogenic HIV/SIV infection. It has been recently shown that natural hosts of SIVs, such as the African green monkey (AGM), avoid damage to the mucosal epithelium through wound healing mechanisms, possibly with the contribution of a unique anti-inflammatory microbiome. Furthermore, these mechanisms are independent of viral replication, and CD4+ T-cell activation or depletion. Future SIV research on natural hosts should focus on further elucidating the anti-inflammatory state of their gut, and the role of microbiome/dysbiosis in the pathogenesis of SIV infection, with the goal of development new regiments or treatments to reduce or even halt the vicious cycle of gut damage and inflammation triggered by pathogenic HIV/SIV infection.

Condomless receptive anal intercourse stands out as the sexual practice with highest risk of HIV-1 infection. Recent studies have suggested that the gut microbiome influences susceptibility to HIV transmission. This review explores recent research on host risk factors, the rectal microbiome composition, local inflammation, and bacteria-derived mediators that may affect HIV transmission. Constitutive host factors such as rectal mucosal structure and immune cell populations in the rectum contribute to increased susceptibility. Changes in the composition of the rectal microbiota, influenced by sexual practices and HIV infection modulate immune activation and inflammation, impacting HIV susceptibility. Bacteria-derived mediators may further influence immune responses and HIV replication in the rectal mucosa. Understanding the role of the rectal microbiome in HIV transmission has important clinical implications. Targeted interventions that modulate the microbiome may reduce susceptibility to HIV transmission by regulating immune responses and inflammation. Further research into the host-microbiome interactions could lead to novel preventive and therapeutic strategies to mitigate HIV transmission.

To summarize the heterogeneity in the elite controllers population with the aim to identify a compatible profile with a persistent HIV remission, making distinction between persistent elite controllers, people with HIV (PWHIV) who permanently maintain virological control in the absence of antiretroviral treatment (ART), and transient elite controllers, PWHIV who eventually lose virological control. For this purpose, it is important to consider the mechanisms and biomarkers that have previously been associated with the maintenance and loss of the natural virological control. Transient elite controllers, before losing virological control, exhibit a distinct metabolomic, proteomic, microRNAs (miRNA), immunological and virological profile compared to persistent elite controllers. In addition to a reduced and less polyfunctional HIV-specific T-cell response, transient elite controllers show a greater proportion of intact proviruses integrated into genic regions. In contrast, persistent elite controllers display a privileged HIV-1 reservoir profile with absence of detected intact proviruses or low proportion of clonal intact proviruses preferentially integrated into genomic features associated with HIV-1 transcriptional repression. According to previous studies, the comprehensive characterization of persistent elite controllers might be crucial to identify other PWHIV with this distinct profile as spontaneously cured.