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Inducing antiretroviral therapy (ART)-free virological control is a critical step toward a human immunodeficiency virus type 1 (HIV-1) cure. In this phase 2a, placebo-controlled, double-blinded trial, 43 people (85% males) with HIV-1 on ART were randomized to (1) placebo/placebo, (2) lefitolimod (TLR9 agonist)/placebo, (3) placebo/broadly neutralizing anti-HIV-1 antibodies (bNAbs) or (4) lefitolimod/bNAb. ART interruption (ATI) started at week 3. Lefitolimod was administered once weekly for the first 8 weeks, and bNAbs were administered twice, 1 d before and 3 weeks after ATI. The primary endpoint was time to loss of virologic control after ATI. The median delay in time to loss of virologic control compared to the placebo/placebo group was 0.5 weeks (P = 0.49), 12.5 weeks (P = 0.003) and 9.5 weeks (P = 0.004) in the lefitolimod/placebo, placebo/bNAb and lefitolimod/bNAb groups, respectively. Among secondary endpoints, viral doubling time was slower for bNAb groups compared to non-bNAb groups, and the interventions were overall safe. We observed no added benefit of lefitolimod. Despite subtherapeutic plasma bNAb levels, 36% (4/11) in the placebo/bNAb group compared to 0% (0/10) in the placebo/placebo group maintained virologic control after the 25-week ATI. Although immunotherapy with lefitolimod did not lead to ART-free HIV-1 control, bNAbs may be important components in future HIV-1 curative strategies. ClinicalTrials.gov identifier: NCT03837756 ., (© 2023. The Author(s).)

Attempts to reduce the human immunodeficiency virus type 1 (HIV-1) reservoir and induce antiretroviral therapy (ART)-free virologic control have largely been unsuccessful. In this phase 1b/2a, open-label, randomized controlled trial using a four-group factorial design, we investigated whether early intervention in newly diagnosed people with HIV-1 with a monoclonal anti-HIV-1 antibody with a CD4-binding site, 3BNC117, followed by a histone deacetylase inhibitor, romidepsin, shortly after ART initiation altered the course of HIV-1 infection ( NCT03041012 ). The trial was undertaken in five hospitals in Denmark and two hospitals in the United Kingdom. The coprimary endpoints were analysis of initial virus decay kinetics and changes in the frequency of CD4 + T cells containing intact HIV-1 provirus from baseline to day 365. Secondary endpoints included changes in the frequency of infected CD4 + T cells and virus-specific CD8 + T cell immunity from baseline to day 365, pre-ART plasma HIV-1 3BNC117 sensitivity, safety and tolerability, and time to loss of virologic control during a 12-week analytical ART interruption that started at day 400. In 55 newly diagnosed people (5 females and 50 males) with HIV-1 who received random allocation treatment, we found that early 3BNC117 treatment with or without romidepsin enhanced plasma HIV-1 RNA decay rates compared to ART only. Furthermore, 3BNC117 treatment accelerated clearance of infected cells compared to ART only. All groups had significant reductions in the frequency of CD4 + T cells containing intact HIV-1 provirus. At day 365, early 3BNC117 + romidepsin was associated with enhanced HIV-1 Gag-specific CD8 + T cell immunity compared to ART only. The observed virological and immunological effects of 3BNC117 were most pronounced in individuals whose pre-ART plasma HIV-1 envelope sequences were antibody sensitive. The results were not disaggregated by sex. Adverse events were mild to moderate and similar between the groups. During a 12-week analytical ART interruption among 20 participants, 3BNC117-treated individuals harboring sensitive viruses were significantly more likely to maintain ART-free virologic control than other participants. We conclude that 3BNC117 at ART initiation enhanced elimination of plasma viruses and infected cells, enhanced HIV-1-specific CD8 + immunity and was associated with sustained ART-free virologic control among persons with 3BNC117-sensitive virus. These findings strongly support interventions administered at the time of ART initiation as a strategy to limit long-term HIV-1 persistence., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Therapeutic strategies are being clinically tested either to eradicate latent HIV reservoirs or to achieve virologic control in the absence of antiretroviral therapy. Attaining this goal will require a consensus on how best to measure the numbers of persistently infected cells with the potential to cause viral rebound after antiretroviral-therapy cessation in assessing the results of cure-directed strategies in vivo. Current measurements assess various aspects of the HIV provirus and its functionality and produce divergent results. Here, we provide recommendations from the BEAT-HIV Martin Delaney Collaboratory on which viral measurements should be prioritized in HIV-cure-directed clinical trials.

Combination antiretroviral therapy (ART) is highly effective in controlling human immunodeficiency virus (HIV)-1 but requires lifelong medication due to the existence of a latent viral reservoir 1,2 . Potent broadly neutralizing antibodies (bNAbs) represent a potential alternative or adjuvant to ART. In addition to suppressing viremia, bNAbs may have T cell immunomodulatory effects as seen for other forms of immunotherapy 3 . However, this has not been established in individuals who are infected with HIV-1. Here, we document increased HIV-1 Gag-specific CD8 + T cell responses in the peripheral blood of all nine study participants who were infected with HIV-1 with suppressed blood viremia, while receiving bNAb therapy during ART interruption 4 . Increased CD4 + T cell responses were detected in eight individuals. The increased T cell responses were due both to newly detectable reactivity to HIV-1 Gag epitopes and the expansion of pre-existing measurable responses. These data demonstrate that bNAb therapy during ART interruption is associated with enhanced HIV-1-specific T cell responses. Whether these augmented T cell responses can contribute to bNAb-mediated viral control remains to be determined.

Combination anti-retroviral therapy (ART) has revolutionized the treatment and prevention of HIV-1 infection. Taken daily, ART prevents and suppresses the infection. However, ART interruption almost invariably leads to rebound viremia in infected individuals due to a long-lived latent reservoir of integrated proviruses. Therefore, ART must be administered on a life-long basis. Here we review recent preclinical and clinical studies suggesting that immunotherapy may be an alternative or an adjuvant to ART because, in addition to preventing new infections, anti-HIV-1 antibodies clear the virus, directly kill infected cells and produce immune complexes that can enhance host immunity to the virus.

Monotherapy of HIV-1 infection with single antiretroviral agents is ineffective because error-prone HIV-1 replication leads to the production of drug-resistant viral variants 1,2 . Combinations of drugs can establish long-term control, however, antiretroviral therapy (ART) requires daily dosing, can cause side effects and does not eradicate the infection 3,4 . Although anti-HIV-1 antibodies constitute a potential alternative to ART 5,6 , treatment of viremic individuals with a single antibody also results in emergence of resistant viral variants 7-9 . Moreover, combinations of first-generation anti-HIV-1 broadly neutralizing antibodies (bNAbs) had little measurable effect on the infection 10-12 . Here we report on a phase 1b clinical trial ( NCT02825797 ) in which two potent bNAbs, 3BNC117 13 and 10-1074 14 , were administered in combination to seven HIV-1 viremic individuals. Infusions of 30 mg kg -1 of each of the antibodies were well-tolerated. In the four individuals with dual antibody-sensitive viruses, immunotherapy resulted in an average reduction in HIV-1 viral load of 2.05 log 10 copies per ml that remained significantly reduced for three months following the first of up to three infusions. In addition, none of these individuals developed resistance to both antibodies. Larger studies will be necessary to confirm the efficacy of antibody combinations in reducing HIV-1 viremia and limiting the emergence of resistant viral variants.

Despite suppressive combination antiretroviral therapy (ART), latent HIV-1 proviruses persist in patients. This latent reservoir is established within 48-72 h after infection, has a long half-life 1,2 , enables viral rebound when ART is interrupted, and is the major barrier to a cure for HIV-1 3 . Latent cells are exceedingly rare in blood (∼1 per 1 × 10 6 CD4 + T cells) and are typically enumerated by indirect means, such as viral outgrowth assays 4,5 . We report a new strategy to purify and characterize single reactivated latent cells from HIV-1-infected individuals on suppressive ART. Surface expression of viral envelope protein was used to enrich reactivated latent T cells producing HIV RNA, and single-cell analysis was performed to identify intact virus. Reactivated latent cells produce full-length viruses that are identical to those found in viral outgrowth cultures and represent clones of in vivo expanded T cells, as determined by their T cell receptor sequence. Gene-expression analysis revealed that these cells share a transcriptional profile that includes expression of genes implicated in silencing the virus. We conclude that reactivated latent T cells isolated from blood can share a gene-expression program that allows for cell division without activation of the cell death pathways that are normally triggered by HIV-1 replication.

Monoclonal antibody 10-1074 targets the V3 glycan supersite on the HIV-1 envelope (Env) protein. It is among the most potent anti-HIV-1 neutralizing antibodies isolated so far. Here we report on its safety and activity in 33 individuals who received a single intravenous infusion of the antibody. 10-1074 was well tolerated and had a half-life of 24.0 d in participants without HIV-1 infection and 12.8 d in individuals with HIV-1 infection. Thirteen individuals with viremia received the highest dose of 30 mg/kg 10-1074. Eleven of these participants were 10-1074-sensitive and showed a rapid decline in viremia by a mean of 1.52 log 10 copies/ml. Virologic analysis revealed the emergence of multiple independent 10-1074-resistant viruses in the first weeks after infusion. Emerging escape variants were generally resistant to the related V3-specific antibody PGT121, but remained sensitive to antibodies targeting nonoverlapping epitopes, such as the anti-CD4-binding-site antibodies 3BNC117 and VRC01. The results demonstrate the safety and activity of 10-1074 in humans and support the idea that antibodies targeting the V3 glycan supersite might be useful for the treatment and prevention of HIV-1 infection.