Ex vivo sensitivity to broadly neutralizing antibodies and anti-CD4 antibody UB-421 of infectious viral isolates from people living with multidrug-resistant HIV.

BACKGROUND: People living with HIV (PLWH) with multidrug-resistant (MDR) viruses have limited therapeutic options and present challenges regarding clinical management. Recent studies have shown that passive transfer of combination broadly neutralizing antibodies (bNAbs) against HIV and anti-domain 1 CD4 antibody UB-421 can sustain virologic suppression in PLWH in the absence of antiretroviral therapy (ART). Yet studies addressing the therapeutic potential of these antibodies and/or detailed characterization of immunologic and virologic parameters in PLWH with MDR HIV are lacking. METHODS: We examined levels of immune activation and exhaustion markers on CD8+ T cells and the intact HIV proviral DNA burden in 11 PLWH with MDR viruses. For comparison purposes, we included a control group consisting of 27 ART-naïve viremic PLWH. In addition, we determined the sensitivity of infectious viral isolates obtained from the participants against eight bNAbs (3BNC117, 10-1074, VRC01, VRC07, N6, 10E8, PGDM1400, and PGT121) and two anti-CD4 antibodies (ibalizumab and UB-421) using a TZM-bl-based neutralization/suppression assay. FINDINGS: The level of intact HIV proviral DNA was comparable between the two groups (P = 0.29). The levels of activation and exhaustion markers PD-1 (P = 0.0019), TIGIT (P = 0.0222), 2B4 (P = 0.0015), CD160 (P = 0.0015), and CD38+/HLA-DR+ (P = 0.0138) were significantly lower in the MDR group. The infectious viral isolates from each study participant with MDR HIV were resistant to at least 2 bNAbs; however, they were sensitive to at least one of the CD4-binding and non-CD4-binding site antibodies. The majority of participants had ibalizumab-sensitive viruses although the isolates from some participants showed reduced sensitivity to ibalizumab. Notably, none of the 93 viral isolates obtained from the participants were resistant to UB-421. INTERPRETATION: Our data suggest that combination therapy with HIV-specific bNAbs and/or UB-421 in the presence of optimized background therapy could potentially provide sustained virologic suppression in PLWH with MDR HIV. However, this therapeutic strategy needs to be evaluated in human clinical trials. FUNDING: Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Impact of Monkeypox Virus Infection on Immune Parameters in a Woman With Human Immunodeficiency Virus Receiving Clinically Effective Antiretroviral Therapy.

We describe the immunologic and virologic impact of monkeypox (mpox) infection in a woman with human immunodeficiency virus (HIV) whose plasma HIV viremia was suppressed by clinically effective antiretroviral therapy. Extensive phenotypic analyses of B and T cells in peripheral blood and biomarkers in plasma showed significant immunologic perturbations despite the presence of mild mpox disease. Dramatic shifts were noted in the frequencies of total B cells, plasmablasts, and plasmablast immunoglobulin isotypes. Flow cytometric analyses showed a dramatic increase in the frequency of CD38+HLA-DR+ CD8+ T cells after mpox infection. Our data offer guidance for future studies involving mpox infection in affected populations.

Effect of Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine Booster on Human Immunodeficiency Virus Reservoirs and Immune Markers.

We investigated effects of the severe acute respiratory syndrome coronavirus 2 (SARV-CoV-2) booster vaccination on human immunodeficiency virus (HIV) reservoir size, immune markers, and host immune responses in people with HIV receiving antiretroviral therapy. Our data suggest that the SARS-CoV-2 booster vaccine is not likely to replenish the persistent HIV reservoir nor provide an immunologic environment to facilitate active HIV expression/replication.

Effect of aging on immune cells in male HIV-infected and -uninfected healthy individuals.

OBJECTIVE: HIV induces immunologic dysfunction in T cells of infected individuals. However, the impact of aging on T cell phenotypes in HIV-infected individuals receiving antiretroviral therapy (ART) has not been fully delineated. We evaluated the relationship between aging and the expression of immune activation and exhaustion markers on CD8 + T cells of age-matched HIV-infected and -uninfected male participants. DESIGN: Levels of immune activation and exhaustion markers on peripheral blood CD8 + T cells of HIV-infected and -uninfected participants were examined. METHODS: 110 HIV-infected aviremic male participants receiving ART and 146 HIV-uninfected male participants were studied. The levels of TIGIT, PD-1, CD38, and CD226 on CD8 + T cells of the study participants were determined by flow cytometry. RESULTS: The level of TIGIT on CD8 + T cells was higher in aviremic HIV-infected compared to uninfected participants ( P  < 0.0001). In contrast, no significant differences were found in the levels of PD-1 and CD38 on CD8 + T cells between the two groups. Statistically significant correlations were observed between age and the levels of TIGIT + and CD38 + CD8 + T cells in both groups; however, no correlation was found between age and the level of PD-1 + CD8 + T cells in HIV-infected participants. Age-stratification of HIV-infected and -uninfected groups did not show any significant differences in the level of PD-1 expression on CD8 + T cells. CONCLUSIONS: The findings of our study highlight the role of aging in the expression of immune markers on CD8 + T cells and have important implications for therapies that target immune checkpoints in HIV-infected individuals.

Correlation Between TIGIT Expression on CD8+ T Cells and Higher Cytotoxic Capacity.

Persistent exposure to antigen leads to T-cell exhaustion and immunologic dysfunction. We examined the immune exhaustion markers T cell immunoglobulin and ITIM domain (TIGIT) and programmed cell death protein 1 (PD-1) in human immunodeficiency virus (HIV)-infected and healthy individuals and the relationship with cytotoxic CD8+ T-lymphocyte activity. Frequencies of TIGIT but not PD-1 were positively correlated with CD8+ T-lymphocyte activity in HIV-aviremic and healthy individuals; however, there was no correlation in HIV-viremic individuals. Transcriptome analyses revealed up-regulation of genes associated with antiviral immunity in TIGIT+CD8+ versus TIGIT-CD8+ T cells. Our data suggest that TIGIT+CD8+ T cells do not necessarily represent a state of immune exhaustion and maintain an intrinsic cytotoxicity in HIV-infected individuals.

Kinetics of Plasma HIV Rebound in the Era of Modern Antiretroviral Therapy.

Historical data regarding time to viral rebound following analytical treatment interruption (ATI) have been used to determine therapeutic efficacy in HIV cure trials; however, such data were collected from studies conducted a decade or more ago and included participants receiving older antiretroviral therapy (ART) regimens with infrequent virologic monitoring. We conducted a study of 22 HIV-infected participants receiving modern ART to determine the kinetics of plasma viral rebound following ATI. Our data suggest that modern ART does not alter kinetics of viral rebound when compared to previous regimens and that immunologic interventions may be necessary to achieve ART-free virologic remission. Clinical Trials Registration ClinicaTrials.gov identifier: NCT03225118.

Broadly neutralizing antibodies suppress HIV in the persistent viral reservoir.

Several highly potent and broadly neutralizing monoclonal antibodies against HIV have recently been isolated from B cells of infected individuals. However, the effects of these antibodies on the persistent viral reservoirs in HIV-infected individuals receiving antiretroviral therapy (ART) are unknown. We show that several HIV-specific monoclonal antibodies--in particular, PGT121, VRC01, and VRC03--potently inhibited entry into CD4(+) T cells of HIV isolated from the latent viral reservoir of infected individuals whose plasma viremia was well controlled by ART. In addition, we demonstrate that HIV replication in autologous CD4(+) T cells derived from infected individuals receiving ART was profoundly suppressed by three aforementioned and other HIV-specific monoclonal antibodies. These findings have implications for passive immunotherapy as an approach toward controlling plasma viral rebound in patients whose ART is withdrawn.

Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy.

Human immunodeficiency virus (HIV) persists in peripheral blood mononuclear cells despite sustained, undetectable plasma viremia resulting from long-term antiretroviral therapy. However, the source of persistent HIV in such infected individuals remains unclear. Given recent data suggesting high levels of viral replication and profound depletion of CD4(+) T cells in gut-associated lymphoid tissue (GALT) of animals infected with simian immunodeficiency virus and HIV-infected humans, we sought to determine the level of CD4(+) T cell depletion as well as the degree and extent of HIV persistence in the GALT of infected individuals who had been receiving effective antiviral therapy for prolonged periods of time. We demonstrate incomplete recoveries of CD4(+) T cells in the GALT of aviremic, HIV-infected individuals who had received up to 9.9 years of effective antiretroviral therapy. In addition, we demonstrate higher frequencies of HIV infection in GALT, compared with PBMCs, in these aviremic individuals and provide evidence for cross-infection between these 2 cellular compartments. Together, these data provide a possible mechanism for the maintenance of viral reservoirs revolving around the GALT of HIV-infected individuals despite long-term viral suppression and suggest that the GALT may play a major role in the persistence of HIV in such individuals.

Pilot study of the effects of intermittent interleukin-2 on human immunodeficiency virus (HIV)-specific immune responses in patients treated during recently acquired HIV infection.

Highly active antiretroviral therapy (HAART) initiated during acute human immunodeficiency virus (HIV) infection may preserve HIV-specific CD4+ T cell responses that are thought to enhance HIV-specific CD8+ T cell function. The present pilot study was designed to determine whether preserved HIV-specific immune responses are augmented by the administration of the immunomodulatory agent interleukin (IL)-2. Nine persons recently (<6 months) infected with HIV were randomized to receive HAART alone or HAART plus 3 cycles of intermittent IL-2 during a 12-month period. Although HAART plus IL-2 significantly increased counts of total and naive CD4+ T cells, compared with HAART alone, there was no increase in CD4+ or CD8+ HIV-specific immune responses. In addition, adjuvant IL-2 therapy did not reduce the pool of HIV-infected resting CD4+ T cells. Thus, although intermittent IL-2 plus HAART quantitatively increased CD4+ T cells, this increase was not selective for HIV-specific CD4+ or CD8+ T cell responses in recently infected persons.