Current Opinion in HIV and AIDS最新文献

Purpose of review: HIV-1 controller individuals represents a model that can be useful for the development of novel vaccines and therapies. Initial studies pointed to the involvement of improved adaptive immunity, however, new emerging evidence suggests the contribution of innate cells to effective antiviral responses in spontaneous controllers. Therefore, understanding the alterations on innate cell subsets might be crucial to develop new effective therapeutic strategies.

Recent findings: Among different innate immune cells, dendritic cell (DC) and natural killer (NK) cell are essential for effective antiviral responses. DC from controllers display improved innate detection of HIV-1 transcripts, higher induction of interferons, higher antigen presenting capacities and increased metabolism and higher capacities to induce polyfunctional CD8+ T-cell responses. Such properties have been mimicked by Toll-like receptor ligands and applied to DC-based immunotherapies in humans and in animal models. NK cells from controllers display higher expression of activating receptors promoting increased antibody-dependent cellular cytotoxicity (ADCC) and natural cytotoxicity activities. Neutralizing antibodies in combination with interleukin-15 superagonist or interferon-α can increase ADCC and cytotoxicity in NK cells from HIV-1 progressors.

Summary: Mimicking DC and NK cell innate profiles in controllers has become a promising strategy to step forward a novel efficient immunotherapy against the HIV-1 infection.

Purpose of review: HIV and antiretroviral therapy (ART) use are linked to an increased incidence of atherosclerotic cardiovascular disease (ASCVD). Immune activation persists in ART-treated people with HIV (PWH), and markers of inflammation (i.e. IL-6, C-reactive protein) predict mortality in this population. This review discusses underlying mechanisms that likely contribute to inflammation and the development of ASCVD in PWH.

Recent findings: Persistent inflammation contributes to accelerated ASCVD in HIV and several new insights into the underlying immunologic mechanisms of chronic inflammation in PWH have been made (e.g. clonal haematopoiesis, trained immunity, lipidomics). We will also highlight potential pro-inflammatory mechanisms that may differ in vulnerable populations, including women, minorities and children.

Summary: Mechanistic studies into the drivers of chronic inflammation in PWH are ongoing and may aid in tailoring effective therapeutic strategies that can reduce ASCVD risk in this population. Focus should also include factors that lead to persistent disparities in HIV care and comorbidities, including sex as a biological factor and social determinants of health. It remains unclear whether ASCVD progression in HIV is driven by unique mediators (HIV itself, ART, immunodeficiency), or if it is an accelerated version of disease progression seen in the general population.

Purpose of review: Immunological studies of spontaneous HIV and simian virus (SIV) controllers have identified virus-specific CD8 +  T cells as a key immune mechanism of viral control. The purpose of this review is to consider how knowledge about the mechanisms that are associated with CD8 +  T cell control of HIV/SIV in natural infection can be harnessed in HIV remission strategies.

Recent findings: We discuss characteristics of CD8 +  T-cell responses that may be critical for suppressing HIV replication in spontaneous controllers comprising HIV antigen recognition including specific human leukocyte antigen types, broadly cross-reactive T cell receptors and epitope targeting, enhanced expansion and antiviral functions, and localization of virus-specific T cells near sites of reservoir persistence. We also discuss the need to better understand the timing of CD8 +  T-cell responses associated with viral control of HIV/SIV during acute infection and after treatment interruption as well as the mechanisms by which HIV/SIV-specific CD8 +  T cells coordinate with other immune responses to achieve control.

Summary: We propose implications as to how this knowledge from natural infection can be applied in the design and evaluation of CD8 +  T-cell-based remission strategies and offer questions to consider as these strategies target distinct CD8 +  T-cell-dependent mechanisms of viral control.

Purpose of review: To summarize the state-of-the-art literature on the epidemiology, disease progression, and mediators of heart failure, tachyarrhythmias, and sudden cardiac death in people living with HIV (PLWH) to inform prevention strategies.

Recent findings: Recent studies corroborate the role of HIV as a risk enhancer for heart failure and arrhythmias, which persists despite adjustment for cardiovascular risk factors and unhealthy behaviors. Immune activation and inflammation contribute to the risk. Heart failure occurs more frequently at younger ages, and among women and ethnic minorities living with HIV, highlighting disparities. Prospective outcome studies remain sparse in PLWH limiting prevention approaches. However, subclinical cardiac and electrophysiologic remodeling and dysfunction detected by noninvasive testing are powerful disease surrogates that inform our mechanistic understanding of HIV-associated cardiovascular disease and offer opportunities for early diagnosis.

Summary: Aggressive control of HIV viremia and cardiac risk factors and abstinence from unhealthy behaviors remain treatment pillars to prevent heart failure and arrhythmic complications. The excess risk among PLWH warrants heightened vigilance for heart failure and arrhythmic symptomatology and earlier testing as subclinical abnormalities are common. Future research needs include identifying novel therapeutic targets to prevent heart failure and arrhythmias and testing of interventions in diverse groups of PLWH.

Purpose of review: To synthesize current evidence on the impact of cardiovascular disease among women living with HIV (WLWH) with a particular focus on disease prevalence, mechanisms and prevention.

Recent findings: HIV-related cardiovascular disease risk is 1.5-fold to 2-fold higher for women than for men. Mechanisms of enhanced risk are multifactorial and include reinforcing pathways between traditional risk factors, metabolic dysregulation, early reproductive aging and chronic immune activation. These pathways influence both the presentation of overt syndromes of myocardial infarction, stroke and heart failure, as well as subclinical disease, such as microvascular dysfunction and cardiac fibrosis. Cardiovascular disease, therefore, remains a consistent threat to healthy aging among WLWH.

Summary: Although no specific prevention strategies exist, patient-centered risk mitigation approaches that are adaptable to the needs of aging individuals are essential to combat disparities in cardiovascular outcomes among WLWH. Further research into the optimal prevention approach for CVD among WLWH, particularly for women living in under-resourced health systems, is needed.

Purpose of review: People with HIV continue to have an excess burden of cardiovascular disease compared to the general population. The reasons for these disparities in cardiovascular disease include HIV-specific risk enhancers, traditional atherosclerotic cardiovascular disease risk factors, and sociodemographic disparities, all of which are ripe targets for intervention.

Recent findings: Accurate risk prediction of atherosclerotic cardiovascular disease remains difficult, and cardiovascular risk for people with HIV may be underestimated in the absence of HIV-specific risk enhancers. Despite this increased cardiovascular risk, people with HIV are undertreated and often placed on inadequate lipid lowering therapy. Structural racism and HIV-related stigma play a role, and provider-level and structural-level interventions to encourage early identification and treatment of persons at high risk are necessary.

Summary: Persons with HIV should be screened with existing cardiovascular risk prediction tools, and those at high risk cardiovascular disease should be promptly referred for lifestyle and pharmacologic interventions as appropriate. System-level implementation research is ongoing in attempts to narrow the gap in cardiovascular care, particularly for vulnerable communities in low resource settings.

Purpose of review: The main reason for the failure of oral preexposure prophylaxis (PrEP) regimens for HIV is poor adherence. Intramuscular cabotegravir was recently approved for PrEP, and a number of other long-acting antiretroviral formulations and products are currently in clinical development. This includes subcutaneous and intravenous injections, implants, and microarray (microneedle) patches, as well as extended duration oral drugs. The success and future uptake of these products will depend on a variety of factors.

Recent findings: Long-acting delivery of antiretroviral agents for PrEP confers significant advantages over short-acting oral delivery. This is exemplified by the superior efficacy of intramuscular cabotegravir given every eight weeks as compared to daily oral co-formulated tenofovir disoproxil fumarate and emtricitabine. There is also evidence for PrEP efficacy for a broadly neutralizing monoclonal antibody given intravenously every eight weeks. One of the leading candidates for long-acting PrEP, islatravir, was being studied as a monthly oral drug or a nonerodable subcutaneous implant inserted for up to 12 months. However, clinical studies of this agent were put on hold in late 2021 because of unanticipated lymphopenia.

Summary: Long-acting antiretroviral products have substantial promise for PrEP and have particular advantages over daily oral drugs based mainly on improved adherence. However, there are barriers to further uptake that include the need for more intensive interaction with systems of healthcare delivery, greater expense and complexity of implementation, and unexpected long-term toxicities.

Purpose of review: To review current laboratory and clinical data on the frequency and relative risk of drug resistance and range of mutations selected from approved and investigational antiretroviral agents used for preexposure prophylaxis (PrEP) of HIV-1 infection, including tenofovir disproxil fumarate (TDF)-based oral PrEP, dapivirine ring, injectable cabotegravir (CAB), islatravir, lenacapavir and broadly neutralizing antibodies (bNAbs).

Recent findings: The greatest risk of HIV-1 resistance from PrEP with oral TDF/emtricitabine (FTC) or injectable CAB is from starting or continuing PrEP after undiagnosed acute HIV infection. By contrast, the dapivirine intravaginal ring does not appear to select nonnucleoside reverse transcriptase inhibitor resistance in clinical trial settings. Investigational inhibitors including islatravir, lenacapavir, and bNAbs are promising for use as PrEP due to their potential for sustained delivery and low risk of cross-resistance to currently used antiretrovirals, but surveillance for emergence of resistance mutations in more HIV-1 gene regions (gag, env) will be important as the same drugs are being developed for HIV therapy.

Summary: PrEP is highly effective in preventing HIV infection. Although HIV drug resistance from PrEP use could impact future options in individuals who seroconvert on PrEP, the current risk is low and continued monitoring for the emergence of resistance and cross-resistance during product development, clinical studies, and product roll-out is advised to preserve antiretroviral efficacy for both treatment and prevention.