Given the limitations of antiretroviral therapy and recent advances in our understanding of HIV persistence during effective treatment, there is a growing recognition that a cure for HIV infection is both needed and feasible. The International AIDS Society convened a group of international experts to develop a scientific strategy for research towards an HIV cure. Several priorities for basic, translational and clinical research were identified. This Opinion article summarizes the group's recommended key goals for the international community.

The question of when to start combination antiretroviral therapy for treatment-naïve patients has always been controversial. This is particularly true in the current era, with major guidelines recommending very different treatment strategies. Despite a lack of clarity regarding the optimal time to begin therapy, there has been a recent shift toward earlier initiation. This more aggressive approach is driven by several observations. First, effective viral suppression with therapy can prevent non-AIDS-related morbidity and mortality. Second, therapy can prevent irreversible harm to the human immune system. Third, therapy may prevent transmission of HIV to others, and thus have a potential public health benefit. For patients who are motivated and willing to initiate early treatment, the collective benefits of early therapy may outweigh the well-documented risks of antiretroviral medications.

Ethical guidelines and recommendations for human subjects research typically focus on protecting the individuals who directly participate in that research. However, additional people, including sex partners of research participants, can also face harms and burdens from medical studies. In human immunodeficiency virus (HIV) cure-related research, a persistent ethical and practical challenge surrounds the use of analytical antiretroviral treatment interruptions. The challenge is usually discussed in relation to risks to study participants, but serious dangers accrue to nonparticipants, including sex partners of study participants. This multidisciplinary supplement relays the risks for nonparticipating sex partners in HIV cure-related studies and addresses the ethical dilemmas raised by these studies, with recommendations for researchers, advocates, sponsors, and oversight bodies.

Discontinued antiretroviral therapy (ART) results in uncontrolled HIV replication in most cases. How the virus population that persists during ART escapes immune control remains unknown. In this issue of the JCI, Mitchell and authors investigated plasmacytoid dendritic cells (pDCs) from the blood of individuals living with HIV. After ART was discontinued and as the virus began to spread, an apparently functional pDC response emerged. Notably, these pDCs were initially capable of producing high levels of type I IFN, but rapidly lost this capacity, even before the virus became readily detectable in blood. This study suggests that dysfunctional pDCs are a key initial mechanism associated with poor HIV control. These innate immune responses might be targeted in the emerging efforts to cure HIV disease.

Intense investigation into the predictors and determinants of post-acute sequelae of SARS-CoV-2 infection (PASC), including 'long COVID', is underway. Recent studies provide clues to the mechanisms that might drive this condition, with the goal of identifying host or virus factors that can be intervened upon to prevent or reverse PASC.

Antiretroviral therapy (ART) is able to suppress HIV-1 replication indefinitely in individuals who have access to these medications, are able to tolerate these drugs, and are motivated to take them daily for life. However, ART is not curative. HIV-1 persists indefinitely during ART as quiescent integrated DNA within memory CD4(+) T cells and perhaps other long-lived cellular reservoirs. In this Review, we discuss the role of the immune system in the establishment and maintenance of the latent HIV-1 reservoir. A detailed understanding of how the host immune system shapes the size and distribution of the viral reservoir should lead to the development of a new generation of immune-based therapeutics, which may eventually contribute to a curative intervention.

Determining the total amount of HIV DNA in people undergoing antiretroviral therapy could accelerate the development of novel therapies and potential cures for HIV infection.

Purpose of review

The present review will highlight some of the recent findings regarding the capacity of HIV-1 to replicate during antiretroviral therapy (ART).

Recent findings

Although ART is highly effective at inhibiting HIV replication, it is not curative. Several mechanisms contribute to HIV persistence during ART, including HIV latency, immune dysfunction, and perhaps persistent low-level spread of the virus to uninfected cells (replication). The success in curing HIV will depend on efficiently targeting these three aspects. The degree to which HIV replicates during ART remains controversial. Most studies have failed to find any evidence of HIV evolution in blood, even with samples collected over many years, although a recent very intensive study of three individuals suggested that the virus population does shift, at least during the first few months of therapy. Stronger but still not definitive evidence for replication comes from a series of studies in which standard regimens were intensified with an integration inhibitor, resulting in changes in episomal DNA (blood) and cell-associated RNA (tissue). Limited drug penetration within tissues and the presence of immune sanctuaries have been argued as potential mechanisms allowing HIV to spread during ART. Mathematical models suggest that HIV replication and evolution is possible even without the selection of fully drug-resistant variants. As persistent HIV replication could have clinical consequences and might limit the efficacy of curative interventions, determining if HIV replicates during ART and why, should remain a key focus of the HIV research community.

Summary

Residual viral replication likely persists in lymphoid tissues, at least in a subset of individuals. Abnormal levels of immune activation might contribute to sustain virus replication.

HIV establishes a reservoir in latently infected T cells, and this reservoir has long hampered curative approaches. A recent study by Descours et al. identifies CD32a as a marker of latently infected T cells, potentially opening the way to the development of strategies that directly target this critical HIV reservoir.

In this discussion, 2 established researchers and clinical trialists debate their opposing views on the utility, benefits, and risks of the use of analytical interruption of antiretroviral therapy as a clinical trial end point and outcome measure in human studies seeking to induce remission of or eradicate human immunodeficiency virus infection.