Relationship of HIV reservoir characteristics with immune status and viral rebound kinetics in an HIV therapeutic vaccine study

Li, Jonathan Z.; Heisey, Andrea; Ahmed, Hayat; Wang, Hongying; Li, Zheng; Carrington, Mary; Wrin, Terri; Schooley, Robert T.; Lederman, Michael M.; Kuritzkes, Daniel R.

doi:10.1097/qad.0000000000000478

Cited by 35 publications

(38 citation statements)

References 33 publications

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“…In any case, we observed changes in the correlations between viral reservoir measurements and HIV-1-specific T cell immune responses before and after vaccinations in both DC-HIV-1 and DC-control groups. No correlations were observed before vaccination, in accordance with the data of other authors who have not found significant associations between the viral reservoir and HIV-specific CD8 T cell counts (19,25). Conversely, a significant inverse correlation was observed after vaccination (and before cART interruption) in vaccinated patients, and a direct correlation was observed in controls.…”

Section: Discussionsupporting

confidence: 81%

“…A recent therapeutic vaccine clinical trial using an autologous dendritic cell-based therapeutic HIV vaccine (similar to our approach) demonstrated an increase of residual viremia and cell-associated RNA after vaccination despite continuous ART (23). Another 2 studies did not find any effect of immunizations on the viral reservoir, despite the fact that both demonstrated an increase in HIV-specific T cell responses (19,24). Finally, Persaud et al (20) found that HIV recombinant poxvirus-based vaccinations administered to in- fected young adults who were receiving durable effective cART resulted in a modest but measurable and statistically significant transient decrease in the frequencies of latently infected CD4 ϩ T cells detected by 40 weeks following the first vaccine dose.…”

Section: Discussionmentioning

confidence: 99%

“…Few therapeutic vaccine clinical trials have tested for the effects of immunizations on the resting CD4 ϩ T cell reservoir in patients receiving cART (19,20,23,24), and only one of them investigated the effects of the changes in the viral reservoir caused by these vaccines after cART interruption (19). A recent therapeutic vaccine clinical trial using an autologous dendritic cell-based therapeutic HIV vaccine (similar to our approach) demonstrated an increase of residual viremia and cell-associated RNA after vaccination despite continuous ART (23).…”

Section: Discussionmentioning

confidence: 99%

“…Few therapeutic vaccine clinical trials have tested for the effect of immunizations on the resting CD4 ϩ T cell reservoir in patients receiving cART (19,20). Li et al studied the relationship between HIV-1 reservoir characteristics and immune status and viral rebound kinetics in HIV-infected patients receiving a therapeutic recombinant adenovirus 5 (rAd5) HIV-1 Gag vaccine (ACTG A5197; ClinicalTrials registration number NCT00080106) (19).…”

mentioning

confidence: 99%

“…Li et al studied the relationship between HIV-1 reservoir characteristics and immune status and viral rebound kinetics in HIV-infected patients receiving a therapeutic recombinant adenovirus 5 (rAd5) HIV-1 Gag vaccine (ACTG A5197; ClinicalTrials registration number NCT00080106) (19). They reported that at study entry, the cell-associated HIV-1 RNA and DNA levels were inversely correlated with the numbers of HIV-1-specific CD4 ϩ interferon gamma (IFN-␥)-producing cells.…”

mentioning

confidence: 99%

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HIV-1 Reservoir Dynamics after Vaccination and Antiretroviral Therapy Interruption Are Associated with Dendritic Cell Vaccine-Induced T Cell Responses

Andrés

Plana

Guardo

et al. 2015

J Virol

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HIV-1-specific immune responses induced by a dendritic cell (DC)-based therapeutic vaccine might have some effect on the viral reservoir. Patients on combination antiretroviral therapy (cART) were randomized to receive DCs pulsed with autologous HIV-1 (n ‫؍‬ 24) (DC-HIV-1) or nonpulsed DCs (n ‫؍‬ 12) (DC-control). We measured the levels of total and integrated HIV-1 DNA in CD4 T cells isolated from these patients at 6 time points: before any cART; before the first cART interruption, which was at 56 weeks before the first immunization to isolate virus for pulsing DCs; before and after vaccinations (VAC1 and VAC2); and at weeks 12 and 48 after the second cART interruption. The vaccinations did not influence HIV-1 DNA levels in vaccinated subjects. After the cART interruption at week 12 postvaccination, while total HIV-1 DNA increased significantly in both arms, integrated HIV-1 DNA did not change in vaccinees (mean of 1.8 log 10 to 1.9 copies/10 6 CD4 T cells, P ‫؍‬ 0.22) and did increase in controls (mean of 1.8 log 10 to 2.1 copies/10 6 CD4 T cells, P ‫؍‬ 0.02) (P ‫؍‬ 0.03 for the difference between groups). However, this lack of increase of integrated HIV-1 DNA observed in the DC-HIV-1 group was transient, and at week 48 after cART interruption, no differences were observed between the groups. The HIV-1-specific T cell responses at the VAC2 time point were inversely correlated with the total and integrated HIV-1 DNA levels after cART interruption in vaccinees (r [Pearson's correlation coefficient] ‫؍‬ ؊0.69, P ‫؍‬ 0.002, and r ‫؍‬ ؊0.82, P < 0. 0001, respectively). No correlations were found in controls. HIV-1-specific T cell immune responses elicited by DC therapeutic vaccines drive changes in HIV-1 DNA after vaccination and cART interruption. (This study has been registered at ClinicalTrials.gov under registration no. NCT00402142.) IMPORTANCEThere is an intense interest in developing strategies to target HIV-1 reservoirs as they create barriers to curing the disease. The development of therapeutic vaccines aimed at enhancing immune-mediated clearance of virus-producing cells is of high priority. Few therapeutic vaccine clinical trials have investigated the role of therapeutic vaccines as a strategy to safely eliminate or control viral reservoirs. We recently reported that a dendritic cell-based therapeutic vaccine was able to significantly decrease the viral set point in vaccinated patients, with a concomitant increase in HIV-1-specific T cell responses. The HIV-1-specific T cell immune responses elicited by this therapeutic dendritic cell vaccine drove changes in the viral reservoir after vaccinations and significantly delayed the replenishment of integrated HIV-1 DNA after cART interruption. These data help in understanding how an immunization could shift the virus-host balance and are instrumental for better design of strategies to reach a functional cure of HIV-1 infection.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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HIV-1 Reservoir Dynamics after Vaccination and Antiretroviral Therapy Interruption Are Associated with Dendritic Cell Vaccine-Induced T Cell Responses

Andrés

Plana

Guardo

et al. 2015

J Virol

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HIV migration between blood plasma and cellular subsets before and after HIV therapy

Choi

Chaillon

et al. 2015

Journal of Medical Virology

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The cellular source of HIV RNA circulating in blood plasma remains unclear. Here, we investigated whether sequence analysis of HIV RNA populations circulating before combination antiretroviral therapy (cART) and HIV DNA populations in cellular subsets (CS) after cART could identify the cellular sources of circulating HIV RNA. Blood was collected from five subjects at cART initiation and again 6 months later. Naïve CD4+ T cells, resting central memory and effector memory CD4+ T cells, activated CD4+ T cells, monocytes, and natural killer cells were sorted using a fluorescence-activated cell sorter. HIV-1 env C2V3 sequences from HIV RNA in blood plasma and HIV DNA in CSs were generated using single genome sequencing. Sequences were evaluated for viral compartmentalization (Fst test) and migration events (MEs; Slatkin Maddison and cladistic measures) between blood plasma and each CS. Viral compartmentalization was observed in 88% of all cellular subset comparisons (range: 77–100% for each subject). Most observed MEs were directed from blood plasma to CSs (52 MEs, 85.2%). In particular, there was only viral movement from plasma to NK cells (15 MEs), monocytes (seven MEs), and naïve cells (five ME). We observed a total of nine MEs from activated CD4 cells (2/9 MEs), central memory T cells (3/9 MEs), and effector memory T cells (4/9 MEs) to blood plasma. Our results revealed that the HIV RNA population in blood plasma plays an important role in seeding various cellular reservoirs and that the cellular source of the HIV RNA population is activated central memory and effector memory T cells.

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HIV-Specific T Cell Responses Are Highly Stable on Antiretroviral Therapy

Trumble

Warren

et al. 2019

Molecular Therapy - Methods & Clinical Development

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HIV infection induces a robust T cell response that is sustained by high viremia, but falls following the onset of antiretroviral therapy (ART). Relatively little has been reported on the subsequent stability of the HIV-specific T cell response in individuals on durable therapy. Such data are critical for powering clinical trials testing T cell-based immunotherapies. In a crosssectional study, HIV-specific T cell responses were detectable by ex vivo interferon (IFN)-g ELISpot (average $1,100 spotforming units [SFUs]/10 6 peripheral blood mononuclear cells) in persons living with HIV (PLWH; n = 34), despite median durable ART suppression of 5.0 years. No substantial association was detected between the summed HIV-specific T cell response and the size of the replication-competent HIV reservoir. T cell responses were next measured in participants sampled weekly, monthly, or yearly. HIV-specific T cell responses were highly stable over the time periods examined; within-individual variation ranged from 16% coefficient of variation (CV) for weekly to 27% CV for yearly sampling. These data were used to generate power calculations for future immunotherapy studies. The stability of the HIV-specific T cell response in suppressed PLWH will enable powered studies of small sizes (e.g., n = 6-12), facilitating rapid and iterative testing for T cell-based immunotherapies against HIV.

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Relationship of HIV reservoir characteristics with immune status and viral rebound kinetics in an HIV therapeutic vaccine study

Cited by 35 publications

References 33 publications

HIV-1 Reservoir Dynamics after Vaccination and Antiretroviral Therapy Interruption Are Associated with Dendritic Cell Vaccine-Induced T Cell Responses

HIV-1 Reservoir Dynamics after Vaccination and Antiretroviral Therapy Interruption Are Associated with Dendritic Cell Vaccine-Induced T Cell Responses

HIV migration between blood plasma and cellular subsets before and after HIV therapy

HIV-Specific T Cell Responses Are Highly Stable on Antiretroviral Therapy

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