A novel vaccine targeting the viral protease cleavage sites protects Mauritian cynomolgus macaques against vaginal SIVmac251 infection

AbstractAfter over three decades of research, an effective anti-HIV vaccine remains elusive. Unconventional and novel vaccine strategies are needed. Here, we report that a vaccine focusing the immune response on the sequences surrounding the 12 viral protease cleavage sites (PCSs) provides greater than 80% protection of Mauritian cynomolgus macaques (MCMs) against repeated intravaginal SIVmac251 challenges. The PCS-specific T cell responses are correlated with vaccine efficacy. The PCS vaccine does not induce immune activation and inflammation known to be associated with increased susceptibility to HIV infection. Machine learning analyses revealed that the immune environment generated by the PCS vaccine predicts vaccine efficacy. Our study demonstrates for the first time that a novel vaccine which targets viral maturation, but lacks full Env and Gag proteins as immunogens, can prevent intravaginal infection in a highly stringent NHP/SIV challenge model. Targeting HIV maturation thus offers a novel approach to developing an effective HIV vaccine.One Sentence SummaryThe anti-PCS T cell responses and the immune environment induced by the novel PCS vaccine are key correlates of vaccine efficacy

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HIV protease cleavage sites vaccine augments quality of T cell responses during ART

Journal of Virus Eradication ◽

10.1016/s2055-6640(20)30667-1 ◽

2017 ◽

Vol 3 ◽

pp. 53-54

Author(s):

R.W. Omange ◽

H. Li ◽

N.P. Toledo ◽

F.A. Plummer ◽

M. Luo

Keyword(s):

T Cell ◽

T Cell Responses ◽

Hiv Protease ◽

Cleavage Sites ◽

Cell Responses ◽

Protease Cleavage ◽

Protease Cleavage Sites

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Strong TH1-biased CD4 T cell responses are associated with diminished SIV vaccine efficacy

Science Translational Medicine ◽

10.1126/scitranslmed.aav1800 ◽

2019 ◽

Vol 11 (519) ◽

pp. eaav1800 ◽

Cited By ~ 7

Author(s):

Venkateswarlu Chamcha ◽

Pradeep B. J. Reddy ◽

Sunil Kannanganat ◽

Courtney Wilkins ◽

Sailaja Gangadhara ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Vaccine Efficacy ◽

Cd4 T Cells ◽

T Cell Responses ◽

Hiv Vaccine ◽

Cd4 T Cell ◽

Cell Responses ◽

Immunodeficiency Virus ◽

Hiv Acquisition

Activated CD4 T cells are a major target of HIV infection. Results from the STEP HIV vaccine trial highlighted a potential role for total activated CD4 T cells in promoting HIV acquisition. However, the influence of vaccine insert-specific CD4 T cell responses on HIV acquisition is not known. Here, using the data obtained from four macaque studies, we show that the DNA prime/modified vaccinia Ankara boost vaccine induced interferon γ (IFNγ+) CD4 T cells [T helper 1 (TH1) cells] rapidly migrate to multiple tissues including colon, cervix, and vaginal mucosa. These mucosal TH1 cells persisted at higher frequencies and expressed higher density of CCR5, a viral coreceptor, compared to cells in blood. After intravaginal or intrarectal simian immunodeficiency virus (SIV)/simian-human immunodeficiency virus (SHIV) challenges, strong vaccine protection was evident only in animals that had lower frequencies of vaccine-specific TH1 cells but not in animals that had higher frequencies of TH1 cells, despite comparable vaccine-induced humoral and CD8 T cell immunity in both groups. An RNA transcriptome signature in blood at 7 days after priming immunization from one study was associated with induction of fewer TH1-type CD4 cells and enhanced protection. These results demonstrate that high and persisting frequencies of HIV vaccine–induced TH1-biased CD4 T cells in the intestinal and genital mucosa can mitigate beneficial effects of protective antibodies and CD8 T cells, highlighting a critical role of priming immunization and vaccine adjuvants in modulating HIV vaccine efficacy.

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A novel HIV vaccine targeting the protease cleavage sites

AIDS Research and Therapy ◽

10.1186/s12981-017-0174-7 ◽

2017 ◽

Vol 14 (1) ◽

Cited By ~ 10

Author(s):

Hongzhao Li ◽

Robert W. Omange ◽

Francis A. Plummer ◽

Ma Luo

Keyword(s):

Hiv Vaccine ◽

Cleavage Sites ◽

Protease Cleavage ◽

Protease Cleavage Sites

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Early CD4+ T Cell Responses Are Associated with Subsequent CD8+ T Cell Responses to an rAd5-Based Prophylactic Prime-Boost HIV Vaccine Strategy

PLoS ONE ◽

10.1371/journal.pone.0152952 ◽

2016 ◽

Vol 11 (4) ◽

pp. e0152952 ◽

Cited By ~ 2

Author(s):

Edouard Lhomme ◽

Laura Richert ◽

Zoe Moodie ◽

Chloé Pasin ◽

Spyros A. Kalams ◽

...

Keyword(s):

T Cell ◽

T Cell Responses ◽

Cd8 T Cell ◽

Hiv Vaccine ◽

Cd4 T Cell ◽

Vaccine Strategy ◽

Cell Responses

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Luteolin-mediated Kv1.3 K+ channel inhibition augments BCG vaccine efficacy against tuberculosis by promoting central memory T cell responses in mice

PLoS Pathogens ◽

10.1371/journal.ppat.1008887 ◽

2020 ◽

Vol 16 (9) ◽

pp. e1008887

Author(s):

Dhiraj Kumar Singh ◽

Ved Prakash Dwivedi ◽

Shashi Prakash Singh ◽

Anjna Kumari ◽

Saurabh Kumar Sharma ◽

...

Keyword(s):

T Cell ◽

Vaccine Efficacy ◽

T Cell Responses ◽

Central Memory ◽

Bcg Vaccine ◽

K Channel ◽

Memory T Cell ◽

Cell Responses ◽

Channel Inhibition

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Designing optimal HIV-vaccine T-cell responses

Current Opinion in HIV and AIDS ◽

10.1097/coh.0000000000000313 ◽

2016 ◽

Vol 11 (6) ◽

pp. 593-600 ◽

Cited By ~ 6

Author(s):

Hendrik Streeck

Keyword(s):

T Cell ◽

T Cell Responses ◽

Hiv Vaccine ◽

Cell Responses

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Long-Term Control of Simian Immunodeficiency Virus (SIV) in Cynomolgus Macaques Not Associated with Efficient SIV-Specific CD8+T-Cell Responses

Journal of Virology ◽

10.1128/jvi.03723-14 ◽

2015 ◽

Vol 89 (7) ◽

pp. 3542-3556 ◽

Cited By ~ 16

Author(s):

Timothée Bruel ◽

Chiraz Hamimi ◽

Nathalie Dereuddre-Bosquet ◽

Antonio Cosma ◽

So Youn Shin ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

T Cell Responses ◽

Cell Depletion ◽

Viral Control ◽

Cell Responses ◽

Cynomolgus Macaques ◽

Hiv 1

ABSTRACTThe spontaneous control of human and simian immunodeficiency viruses (HIV/SIV) is typically associated with specific major histocompatibility complex (MHC) class I alleles and efficient CD8+T-cell responses, but many controllers maintain viral control despite a nonprotective MHC background and weak CD8+T-cell responses. Therefore, the contribution of this response to maintaining long-term viral control remains unclear. To address this question, we transiently depleted CD8+T cells from five SIV-infected cynomolgus macaques with long-term viral control and weak CD8+T-cell responses. Among them, only one carried the protective MHC allele H6. After depletion, four of five controllers experienced a transient rebound of viremia. The return to undetectable viremia was accompanied by only modest expansion of SIV-specific CD8+T cells that lacked efficient SIV suppression capacityex vivo. In contrast, the depletion was associated with homeostatic activation/expansion of CD4+T cells that correlated with viral rebound. In one macaque, viremia remained undetectable despite efficient CD8+cell depletion and inducible SIV replication from its CD4+T cellsin vitro. Altogether, our results suggest that CD8+T cells are not unique contributors to the long-term maintenance of low viremia in this SIV controller model and that other mechanisms, such as weak viral reservoirs or control of activation, may be important players in control.IMPORTANCESpontaneous control of HIV-1 to undetectable levels is associated with efficient anti-HIV CD8+T-cell responses. However, in some cases, this response fades over time, although viral control is maintained, and many HIV controllers (weak responders) have very low frequencies of HIV-specific CD8+T cells. In these cases, the importance of CD8 T cells in the maintenance of HIV-1 control is questionable. We developed a nonhuman primate model of durable SIV control with an immune profile resembling that of weak responders. Transient depletion of CD8+cells induced a rise in the viral load. However, viremia was correlated with CD4+T-cell activation subsequent to CD8+cell depletion. Regain of viral control to predepletion levels was not associated with restoration of the anti-SIV capacities of CD8+T cells. Our results suggest that CD8+T cells may not be involved in maintenance of viral control in weak responders and highlight the fact that additional mechanisms should not be underestimated.

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