Amelia N. Deitchman

Persistence of SARS-CoV-2 has been proposed as a biological driver of Long COVID, a disabling chronic illness with no proven treatments. We conducted an exploratory, placebo-controlled, double-blind, 2:1 randomized mechanistic trial (NCT05877508) of the SARS-CoV-2-specific monoclonal antibody AER002 in 36 participants who met the World Health Organization case definition of Long COVID. After baseline characterization, participants received a single infusion and were followed for 360 days. The primary endpoint was the PROMIS-29 Physical Health Summary Score (PHSS) at 90 days; secondary and exploratory endpoints included patient-reported and objective measures of physical and neurocognitive function as well as blood-, imaging-, and tissue-based biomarkers. While AER002 was safe and well tolerated, no significant differences in physical health, quality of life, objective measures of physical function or cognition, or blood-based biomarkers were demonstrated between the treatment and control arms. In a post-hoc analysis, participants with a lower baseline SARS-CoV-2 antibody level and higher drug exposure were more likely to perceive treatment benefit based on the Patient Global Impression of Change scale ( p < 0.05 for anti-S, S1, and RBD). Although AER002 was not efficacious in this proof-of-concept study, our findings could inform future trials using monoclonal antibodies to target viral persistence in Long COVID.

Passively transferred SARS-CoV-2 maternal antibody (MatAb) provides significant protection against COVID-19 hospitalization in infancy, however the impact of MatAb presence and prior COVID-19 infection on the immunogenicity and longitudinal durability of SARS-CoV-2 mRNA vaccination in young children, is not known. Here, we evaluate pre- and post-vaccination and longitudinal SARS-CoV-2 antibody responses of 66 young children aged six months to four years of age. We found that young children mount a robust immune response to mRNA SARS-CoV-2 vaccines regardless of prior infection history. In contrast, MatAb presence at the time of vaccination significantly inhibited the induction and long-term durability of vaccine-induced humoral immunity. Post-primary vaccine IgG levels were not significantly different by biological sex or vaccine manufacturer. MatAb interference resolved by twelve months of age; strategic booster dosing or optimized primary series timing may overcome maternal antibody inhibition and optimize immunologic protection in young children.

Despite significant advances in antiretroviral therapy, the need for a cure for HIV persists because of factors such as long-term antiretroviral therapy-related comorbidities, disease stigma, and inequities in access to care. Most cure efforts focus on inducing durable HIV remission (antiretroviral therapy-free viral control) either by augmenting immune function or reducing the HIV reservoir. In this review, we highlight immune-based cure interventions currently under investigation with a particular focus on those that have demonstrated the ability to induce durable HIV remission after analytic treatment interruption, here termed “post-intervention control”. While current cure interventions are generally complex, expensive, and not easily scalable, they provide critical “proof of principle” that a cure for HIV is possible. Continuing to make studies of HIV cure a funding priority is important, we believe, as continued optimization of cure interventions should eventually lead to a cure that is simple, safe, effective, affordable, and scalable. In addition, we highlight critical features in clinical trial design and pharmacokinetics/pharmacodynamics that should be considered prior to clinical trial implementation.

The identification of therapeutic strategies to induce sustained antiretroviral therapy (ART)-free control of HIV infection is a major priority ¹ . Combination immunotherapy including HIV vaccination, immune stimulation, latency reversal and passive transfer of broadly neutralizing antibodies (bNAbs) has shown promise in non-human primate models ^2–6 , but few studies have translated such approaches into people. Here we performed a single-arm, proof-of-concept study in ten people living with HIV on ART, combining the following three approaches: (1) therapeutic vaccination with an HIV Gag conserved element-targeted DNA + IL-12 prime/modified vaccinia Ankara (MVA) boost regimen followed by (2) administration of two bNAbs (10-1074, VRC07-523LS) and a toll-like receptor 9 agonist (lefitolimod) during ART suppression, followed by (3) repeat bNAb administration at the time of ART interruption (Clinicaltrials.gov: NCT04357821 ). Seven out of the ten participants exhibited post-intervention control after pausing ART, independent of residual bNAb plasma levels. Robust expansion of activated CD8 ⁺ T cells early in response to rebounding virus correlated with a lower median viral load after peak viraemia off ART. These data suggest that combination immunotherapy approaches might prove effective in inducing sustained control of HIV by slowing rebound and improving CD8 ⁺ T cell responses, and that these approaches should continue to be optimized.

HIV continues to impose a significant global burden despite success of effective antiretroviral therapy and pre-exposure prophylaxis (PrEP), due to stigma, access, and continuity of treatment that impact real-world effectiveness. Broadly neutralizing antibodies (bNAbs) are novel monoclonal antibody therapeutics being studied for long-acting ART and PrEP, and part of curative HIV regimens. Clinical translation for dose optimization remains a major challenge for the development of these therapeutics. Further, methods to characterize tissue levels of these agents are limited and often impractical due to the need for invasive tissue biopsies. Here we demonstrate the ability of serial whole body positron emission tomography (PET) imaging, following microdosing of the bNAb VRC01 in people without HIV, coupled with physiological-based pharmacokinetic (PBPK) modeling, to accurately predict therapeutic plasma, tissue exposure and prevention efficacy in two major VRC01 prevention trials. Based on our PBPK model, we determined a >51-fold anorectal tissue VRC01 level:inhibitory concentration (IC ₈₀ ) target would achieve 90% prevention efficacy compared to >200 based on plasma levels in the primary trial analysis. Thus, these PET-PBPK approaches are promising for noninvasive determination of bNAb penetration more closely linked with concentrations needed to prevent virus acquisition, and may be leveraged to improve efficient development of bNAbs.

Gene-modification therapies are at the forefront of HIV-1 cure strategies. Chimeric antigen receptor (CAR)-T cells pose a potential approach to target infected cells during antiretroviral therapy or following analytical treatment interruption (ATI). However, there are technical challenges in the quantification of HIV-1-infected and CAR-T cells in the setting of lentiviral CAR gene delivery and also in the identification of cells expressing target antigens. First, there is a lack of validated techniques to identify and characterize cells expressing the hypervariable HIV gp120 in both ART-suppressed and viremic individuals. Second, close sequence homology between lentiviral-based CAR-T gene modification vectors and conserved regions of HIV-1 creates quantification challenges of HIV-1 and lentiviral vector levels. Consideration needs to be taken into standardizing HIV-1 DNA/RNA assays in the setting of CAR-T cell and other lentiviral vector-based therapies to avoid these confounding interactions. Lastly, with the introduction of HIV-1 resistance genes in CAR-T cells, there is a need for assays with single-cell resolution to determine the competence of the gene inserts to prevent CAR-T cells from becoming infected in vivo. As novel therapies continue to arise in the HIV-1 cure field, resolving these challenges in CAR-T-cell therapy will be crucial.

BACKGROUND. The presence and reactivation of chronic viral infections, such as EBV, CMV, and HIV, have been proposed as potential contributors to long COVID (LC), but studies in well-characterized postacute cohorts of individuals with COVID-19 over a longer time course consistent with current case definitions of LC are limited. METHODS. In a cohort of 280 adults with prior SARS-CoV-2 infection, we assessed the presence and types of LC symptoms and prior medical history (including COVID-19 history and HIV status) and performed serological testing for EBV and CMV using a commercial laboratory. We used covariate-adjusted binary logistic regression models to identify independent associations between variables and LC symptoms. RESULTS. We observed that LC symptoms, such as fatigue and neurocognitive dysfunction, at a median of 4 months following initial diagnosis were independently associated with serological evidence suggesting recent EBV reactivation (early antigen–diffuse IgG positivity) or high nuclear antigen (EBNA) IgG levels but not with ongoing EBV viremia. Serological evidence suggesting recent EBV reactivation (early antigen–diffuse IgG positivity) was most strongly associated with fatigue (OR = 2.12). Underlying HIV infection was also independently associated with neurocognitive LC (OR = 2.5). Interestingly, participants who had serologic evidence of prior CMV infection were less likely to develop neurocognitive LC (OR = 0.52). CONCLUSION. Overall, these findings suggest differential effects of chronic viral coinfections on the likelihood of developing LC and association with distinct syndromic patterns. Further assessment during the acute phase of COVID-19 is warranted. TRIAL REGISTRATION. Long-term Impact of Infection with Novel Coronavirus; ClinicalTrials.gov NCT04362150. FUNDING. This work was supported by NIH/National Institute of Allergy and Infectious Diseases grants (3R01AI141003-03S1, R01AI158013, and K24AI145806); the Zuckerberg San Francisco General Hospital Department of Medicine and Division of HIV, Infectious Diseases, and Global Medicine; and the UCSF-Bay Area Center for AIDS Research (P30-AI027763).

The efficacy of HIV pre-exposure prophylaxis (PrEP) is high in men who have sex with men, but much more variable in women, in a manner largely attributed to low adherence. This reduced efficacy, however, could also reflect biological factors. Transmission to women is typically via the female reproductive tract (FRT), and vaginal dysbiosis, genital inflammation, and other factors specific to the FRT mucosa can all increase transmission risk. We have demonstrated that mucosal fibroblasts from the lower and upper FRT can markedly enhance HIV infection of CD4+ T cells. Given the current testing of tenofovir disoproxil fumarate, cabotegravir, and dapivirine regimens as candidate PrEP agents for women, we set out to determine using in vitro assays whether endometrial stromal fibroblasts (eSF) isolated from the FRT can affect the anti-HIV activity of these PrEP drugs. We found that PrEP drugs exhibit significantly reduced antiviral efficacy in the presence of eSFs, not because of decreased PrEP drug availability, but rather of eSF-mediated enhancement of HIV infection. These findings suggest that drug combinations that target both the virus and infection-promoting factors in the FRT—such as mucosal fibroblasts—may be more effective than PrEP alone at preventing sexual transmission of HIV to women.

A major obstacle to achieving long-term antiretroviral (ART) free remission or functional cure of HIV infection is the presence of persistently infected cells that establish a long-lived viral reservoir. HIV largely resides in anatomical regions that are inaccessible to routine sampling, however, and non-invasive methods to understand the longitudinal tissue-wide burden of HIV persistence are urgently needed. Positron emission tomography (PET) imaging is a promising strategy to identify and characterize the tissue-wide burden of HIV. Here, we assess the efficacy of using immunoPET imaging to characterize HIV reservoirs and identify anatomical foci of persistent viral transcriptional activity using a radiolabeled HIV Env-specific broadly neutralizing antibody, ⁸⁹Zr-VRC01, in HIV-infected individuals with detectable viremia and on suppressive ART compared to uninfected controls (NCT03729752). We also assess the relationship between PET tracer uptake in tissues and timing of ART initiation and direct HIV protein expression in CD4 T cells obtained from lymph node biopsies. We observe significant increases in ⁸⁹Zr-VRC01 uptake in various tissues (including lymph nodes and gut) in HIV-infected individuals with detectable viremia (N = 5) and on suppressive ART (N = 5) compared to uninfected controls (N = 5). Importantly, PET tracer uptake in inguinal lymph nodes in viremic and ART-suppressed participants significantly and positively correlates with HIV protein expression measured directly in tissue. Our strategy may allow non-invasive longitudinal characterization of residual HIV infection and lays the framework for the development of immunoPET imaging in a variety of other infectious diseases.