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Director, The Peter Doherty Institute for Infection and Immunity
Professor of Infectious Diseases
University of Melbourne
Consultant Infectious Diseases Physician
Alfred Hospital and Royal Melbourne Hospital
Sharon R. Lewin, AO, FRACP, PhD, FAHMS, has disclosed that she has received consulting fees form Abivax, Aelix, Bionor, Bristol-Myers Squibb, Esfam Biotech, Gilead Sciences, Immunocore, InnaVirVax, Merck Sharpe & Dohme, Vaxxinity, and ViiV.
Throughout the HIV epidemic, Australia has stood out as a leader and global model in its response. Today, Australia is one of few countries that has achieved the UNAIDS three 90s goals for HIV elimination. In Australia in 2019, 90% of people with HIV (PWH) were diagnosed, 92% of those diagnosed received treatment, and 97% of those receiving treatment had undetectable HIV-1 RNA. In 2020, Australia reported only 633 new HIV diagnoses, which continues the trend of a reduction in new infections each year since 2014. Despite the continuing downward trend in new infections and remarkable progress in eliminating additional HIV infections, PWH in Australia, as everywhere across the globe, continue to manage the day-to-day reality of living with an incurable infectious disease that requires lifelong treatment. For this reason, there is great interest in HIV cure research, even in regions like Australia that are nearing the goal of eliminating new infections. This commentary focuses on several interesting presentations related to functional cure of HIV reported at the 2022 Conference on Retroviruses and Opportunistic Infection (CROI), including new insights into understanding the viral reservoir.
Intact Provirus Accumulation at Deep Latency Sites During Long-term ART
A new technology made possible through technical breakthroughs such as parallel HIV-1 RNA, integration site, and proviral sequencing (PRIP-seq) allows assessment of the extent and location of viral latency. Seiger and colleagues used full-length individual proviral sequencing (FLIP-Seq) and matched integration site and proviral sequencing (MIP-Seq) on samples from 8 individuals on long-term suppressive antiretroviral therapy (ART) (median: 20 years; ≥15 years with undetectable HIV-1 RNA) and compared the results with samples from 43 people on ART for a shorter duration (median: 9 years). The results demonstrated that over time, there is selection of intact virus that is more deeply latent, that is, harder to activate as a result of integration into repressive heterochromatin locations. This chromosomal integration pattern was similar to that observed in elite controllers. The key question is whether long-term ART reaches a point at which latency is deep enough to prevent viral rebound if the person discontinues ART. Future work using these assays, together with interruption of ART, may allow us to address this question.
Combination Therapies: Latency Reversal Agents and Broadly Neutralizing Antibodies
It is now clear that there is no single intervention that will eliminate HIV latency. Therefore, approaches that use more than one intervention, for example, a latency reversing agent used with either antibodies, a vaccine, or immunomodulating agent, are now being tested. Timing of administration regarding ART initiation is also being considered.
Gunst and colleagues assessed the effects of romidepsin (a histone deacetylase inhibitor used as a latency reversing agent) with 3BNC117 (a broadly neutralizing antibody) in the phase Ib/IIa eCLEAR study. In contrast to earlier studies, the intervention was administered at the time of ART initiation, rather than in people on stable ART.
Four interventions were assessed in 60 participants, all given at the time of initiating integrase strand transfer inhibitor–based ART: no additional therapy, romidepsin alone (given on Days 10, 17, and 24), 3BNC117 alone (given on Days 7 and 21), and romidepsin plus 3BNC117 (same schedules as for single treatment arms). The viral reservoir was measured after 56 weeks of ART, and participants had the option of interrupting ART at that time, well after the antibodies would have been washed out of circulation. The results showed a reduction in cells expressing HIV protein in participants who received combination treatment. HIV-specific CD8+ T-cells were increased in participants who received 3BNC117 alone or in combination with romidepsin. Of interest, there was a significant delay in time to viral rebound in the subset of participants who underwent a treatment interruption if their virus was sensitive to 3BNC117 compared to those with virus resistant to 3BNC117. One participant who received ART plus romidepsin plus 3BNC117 has maintained undetectable HIV-1 RNA for 3.7 years after discontinuing ART. Although this was a relatively small exploratory study, the investigators showed a reduction in the size of the reservoir and enhanced immune function when 3BNC117 was administered at the time of ART initiation. In some participants, there was a delay in viral rebound after analytical treatment interruption although the investigators did not report which intervention was specifically key to achieving this outcome. Further studies assessing cure interventions should be performed in those who are newly starting ART, in addition to those on stable ART.
The New York Patient
The most widely talked about presentation involved the New York patient. This was the third reported case of HIV remission following transplantation of CCR5 D32 homozygous stem cells. The 2 earlier reports of remission—Timothy Brown (the Berlin patient) and Adam Castillejo (the London patient)—were men with HIV who had received adult stem cells from a donor who was HLA matched and also carried the CCR5 D32 mutation—which is a very difficult donor to find. The New York patient is a mixed-race woman who was diagnosed with HIV and initiated ART in 2013. She was subsequently diagnosed with high-risk acute myeloid leukemia in 2017 and underwent transplantation with HLA-matched adult stem cells combined with cord blood from a CCR5 D32 homozygous donor. HIV DNA, plasma HIV-1 RNA, HIV antibody, and infectious virus were all measurable at the time of transplantation. By Day 100 following transplantation, there was full chimerism with the cord blood cells and all markers of the reservoir became negative: HIV antibodies and HIV-specific T-cells were no longer measurable and no replication competent virus could be isolated. After 3 years, the patient stopped ART and HIV-1 RNA has remained undetectable with no instances of viral rebound for 14 months. There was no evidence of graft-vs-host disease.
This report is exciting because the procedure used (ie, combining cord blood cells with the CCR5 D32 mutation together with adult stem cells) is more broadly applicable for people with HIV and cancer than finding an adult stem cell donor homozygous for the CCR5 D32 mutation. Cord blood can be banked allowing for screening of many donors for the CCR5 D32 mutation. In addition, HLA matching is less stringent for cord blood leading to reduced toxicity and incidence of graft-vs-host disease. Using this method means that a larger pool of people with HIV on ART and hematologic malignancy would be eligible for CCR5 D32 cord blood stem cell transplantation and possible HIV cure. Although stem cell transplantation cannot be used in PWH on ART without cancer, the case report confirms that a cure for HIV is possible and provides further support for approaches such as gene therapy.
Did you follow the reports on HIV cure presented at the recent CROI? What reports were the most interesting to you? Join the discussion by posting a comment.
For more details on this and other key HIV issues from CROI 2022, review more CCO Conference Coverage, including Capsule Summary slidesets and other ClinicalThought commentaries highlighting US and global perspectives.