The Fourth Symposium of Grand Challenges on HIV (2023.12.28)

The Fourth Symposium of Grand Challenges on HIV was held on December 28, 2023, in Beijing, China. Fu-Sheng Wang (the National Clinical Research Center for Infectious Disease) and Zhang Linqi (Tsinghua University School of Medicine), as the chairpersons of the conference, organized this meeting. At the conference, almost all famous top scientists and clinicians in Acquired Immune Deficiency Syndrome (AIDS) from China (Figure 1) were invited to present and discuss the most recent advances in the science of a cure for human immunodeficiency virus (HIV) and share new technologies, new therapies and new achievements, and hoping to make major breakthroughs in AIDS intervention and AIDS functional cure.Figure 1: The 4th Symposium of Grand Challenges on HIV (2023.12.28 Beijing).1. Overview of the HIV epidemic and clinical problems According to the Joint United Nations Programmed on HIV/AIDS (UNAIDS) estimates, the number of HIV-infected individuals 50 years and older worldwide has increased from 5.4 million in 2015 to 8.1 million in 2020. The proportion of HIV-infected individuals 50 years and older has risen significantly from 8% in 2000 to 24% in 2020.[1] Mengjie Han (Chinese Center for Disease Control and Prevention) presented the epidemiology of infection with HIV at the conference. In 2022, China reported 107,000 HIV/AIDS cases, and by the end of 2022, the reported survival HIV/AIDS cases were 1.223 million. In the past decade, the proportion of reported cases 50 years and older in China has shown a continuously increasing trend, with male cases 50 years and older rising from 19.57% in 2010 to 44.39% in 2022, and female cases 50 years and older rising from 16.26% in 2010 to 62.78% in 2022. Older HIV-infected individuals are more likely to experience multiple diseases compared with younger HIV-infected individuals, and they have a higher proportion of comorbidities with non HIV-infected elderly individuals of similar age. Therefore, older HIV-infected individuals face more health care needs. Because there is no unified definition of immune reconstitution failure in HIV infection, Taisheng Li (Peking Union Medical College Hospital) released and explained the expert consensus on immune reconstitution failure in this conference. His research shows that the application of traditional Chinese medicine Tripterygium wilfordii inhibits immune activation and improves immune reconstitution.[2] The proportion of HIV coinfected with chronic hepatitis B is high. Linghua Li (Guangzhou Eighth People's Hospital) analyzed the factors related to the negative conversion of hepatitis B surface antigen (HBsAg) in the HIV/HBV coinfection cohort. They found that baseline HBsAg levels <1500 COI, HBV genotype B, and elevated ALT levels exceeding a 2-fold upper limit within 6 months of treatment were crucial factors affecting HBsAg clearance. Treatment with a tenofovir alafenemide fumarate regimen for 48 weeks can achieve a higher HBsAg clearance rate.[3] Tianjun Jiang (the Fifth Medical Centre of Chinese PLA General Hospital) interpreted China's Expert Consensus on Rapid Initiation of Antiviral Therapy for AIDS and tried to start antiviral therapy within 30 days after diagnosis. If infected people with advanced diseases have no contraindication to begin antiviral therapy, start treatment within 7 days after diagnosis. The global rapid launch of ART projects has confirmed multiple benefits. The HIV strains are diverse and complex. The 01AE subtype is a vital strain prevalent in China. Yiming Shao (Chinese Center for Disease Control and Prevention) found that the 01AE subtype is divided into seven independent evolutionary clusters, with 1–3 prevalent in the opposite sex/drug user population, mainly in the south of China. Four-five is mainly located in Beijing and Northeast China, with a prevalence of homosexual. Six and seven are mainly transmitted by the opposite sex in Fujian and Yunnan provinces. In addition, there are many non-clustered strain sequences.[4] Yiming Shao emphasized that HIV monitoring in our country should be updated from serological and molecular epidemiology to phenotype and pathogenicity monitoring in a timely manner, providing early warning and technical support for precise prevention and control. 2. Novel insights into HIV latency The persistence of HIV reservoirs remains a major barrier to an HIV cure. By using a CRISPR (clustered regularly interspaced short palindromic repeats) screening system, Kai Deng (Sun Yet-Sen University) and his group found that NUDT21 was involved in latent HIV infection. Knockdown of NUDT21 promotes the reactivation of latent HIV reservoir in CD4 T cells. He also shared his laboratory's discovery of an induced CD8 T (iCD8 T) cell subset generated from CD4 T cells upon HIV infection. These iCD8 T cells may also be an important part of the HIV reservoir and warrant further investigations. Guoxin Liang (The First Hospital of China Medical University) talked about the role of keratin protein KRT72 (Keratin 72) in suppressing HIV infection in resting CD4 T cells. Resting CD4 T cells are an essential part of HIV reservoir, but HIV replication maintained a low replication status in resting CD4 T cells. He found that KRT72 could be a novel host-restricting factor that counteracted the effect of Vpx on promoting the transcription of HIV in resting CD4 T cells. Dan Yu (Beijing Children's Hospital, Capital Medical University) presented data on the role of PRMT3 (protein arginine methyltransferases 3) for antagonizing HIV latency reversal. By using a novel dCas9 screen system, she identified PRMT3 as a potential host factor that could regulate HIV transcription. She found that PRMT3 could bind to the LTR regions, and inhibition of PRMT3 could suppress Tat-induced activation of HIV transcription. Chen Huan (The First Hospital of Jilin University) presented her discovery of high RPLP1 (Ribosomal Protein Lateral Stalk Subunit P1) expression in HIV-infected long-term nonprogressors, and she identified RPLP1 was a novel transcriptional repressor of HIV subtype B strains and RPLP1 impeded the interaction of transcription factor C/EBPβ with LTR regions. Huanzhang Zhu (Fudan University) presented a possible alternative therapeutic approach to excise HIV provirus from infected and latently infected human T cells by using specially designed zinc-finger nucleases to target sequences within the LTR regions.[5] In addition, he showed the data that ingenol derivatives extracted from Euphorbia kansui have dual functions: reactivation of latent HIV-1 and inhibition of HIV-1 infection.[6] 3. Efforts toward HIV functional cure 3.1. Cell therapy Hongzhou Lu (Shenzhen Third People's Hospital) summarized the application of chimeric antigen receptors T (CAR-T) cell therapy in treating infectious diseases. He also presented data from his team on the treatment of HIV using multifunctional CAR-T cells. His group found that CAR-T cell therapy was well tolerated, decreased the cell-associated HIV-RNA, and exerted selective pressure on HIV latent reservoir. Hui Zhang (Sun Yet-Sen University) and his team shared the clinical trial results on HIV-specific CAR-T cell therapy to eliminate the HIV reservoir (clinical trial identifier: NCT03240328). They demonstrated that HIV-1-specific CAR-T cell therapy showed good clinical safety and reduced the size of the latent HIV viral reservoir.[7] Interestingly, they observed that CAR-T cell therapy also improved the reconstitution of HIV-specific immune function. 3.2. Neutralizing antibody Broadly neutralizing antibodies (bNAbs) can neutralize HIV-1 and target infected cells for elimination. Zhiwei Wu (Medical School of Nanjing University) presented his laboratory's discovery of Nb457-HSA-457 with a heterotrimeric bispecific configuration, which exhibited potent neutralization potency against different HIV strains in vitro and provided in vivo protection against HIV in HuPBL-NCG mice. These findings warrant further evaluation in clinical trials. 3.3. Fusion inhibitors Jing Xue (Chinese Academy of Medical Science, Peking Union Medical College) presented the early treatment effect of LP-98, a lipopeptide HIV fusion inhibitor,[8] as a postexposure prophylaxis using the rhesus macaque model. LP-98 postexposure prophylaxis effectively protected the monkeys from both intrarectal and intravenous infections, and the earlier the treatment was initiated, the higher the protection rate. In addition, several pathways, including genes related to lipoprotein particle response, cellular response to lipoprotein particle stimulus and detection of biotic stimulus may contribute to the defensive process of LP-98's early treatment protection. Yuxian He (Chinese Academy of Medical Sciences) summarized progress on new strategies for HIV gene therapy targeting viral membrane fusion mechanisms. Using lentiviral gene therapy vectors, his lab anchors antiviral fusion peptides, neutralizing antibodies, or bifunctional molecules to the surface of target cells via glycosylphosphatidylinositol anchors. This approach enables modified cells to exhibit broad-spectrum, multipathway antiviral actions, including inhibiting HIV fusion and entry, blocking virus transmission between cells, and affecting the generation and infectivity of progeny viruses.[9] The development of potent HIV-resistant cells provides new ideas for the functional cure of AIDS. 3.4. Vaccines There is an urgent need to develop effective HIV vaccines to halt the transmission of HIV, as well as therapeutic vaccines that can control or even eliminate HIV. Ling Chen (Guangzhou Laboratory) discussed the progress in HIV vaccine research and provided insights into mucosal vaccines. Zhiwei Chen (University of Hong Kong) presented a third-generation PD1 DNA vaccine that has unique efficacy, achieving over 6 years of HIV prevention and viral control without antiviral treatment in monkeys, thus meeting preliminary goals for functional cure. Mechanistic studies further revealed that this vaccine induces central memory T cells, critical precursors for generating CD8+ T cells that clear HIV in mucosal tissues.[10] Moreover, Xia Jin (Immuno Cure BioTech Ltd) presented a follow-up phase I human clinical trial of a third-generation DNA vaccine that incorporates DC-targeting strategy and conserved HIV-1 mosaic Gag antigens. Preliminary data indicate that the DNA vaccine is safe, with no vaccine-related severe adverse events, and that most vaccine recipients generated potent T cell immune responses. Further clinical investigation of such a vaccine is warranted. Envelope protein immunogens in their natural trimeric form are more effective in inducing cross-reactive neutralizing antibodies. Xianghui Yu's (Jilin University) team developed a new structurally stable gp120 trimer immunogen through dual sequence and structural design. By exploring several immunogenicity enhancement strategies, including novel nanoparticle adjuvants, nanoparticle vaccine design and optimization, and virus vector vaccines, immunization with the gp120 trimer immunogen induced highly effective and broad-spectrum neutralizing antibodies through mechanisms such as enhancing germinal center responses and activating cellular immune reactions.[11] Caijun Sun (Sun Yat-Sen University) presented a novel therapeutic HIV vaccine strategy using optimized HSV vectors. The recombinant vectors could elicit strong HIV antigen-specific humoral and cellular immune responses in mice. Interestingly, the modified HSV vectors (especially HSV-Δicp34.5) effectively activated latent HIV. The in vivo therapeutic/cure effects were further verified in the Macaque/SIV infection model. These findings suggest that HSV-Δicp34.5 holds promise as a therapeutic AIDS vaccine and, when used in conjunction with ART drugs, could achieve the goal of functionally curing AIDS. Participants had a heated discussion on the current hot issues in the field of AIDS. This meeting identified multiple promising new avenues for clinical issues and scientific collaboration. To make progress in this challenging research field, extensive and ambitious cooperation, investment, and innovation are needed.