Broad HIV-1 inhibition in vitro by vaccine-elicited CD8+ T cells in African adults

Abstract

We are developing a pan-clade HIV-1 T-cell vaccine HIVconsv, which could complement Env vaccines for prophylaxis and be a key to HIV cure. Our strategy focuses vaccine-elicited effector T-cells on functionally and structurally conserved regions (not full-length proteins and not only epitopes) of the HIV-1 proteome, which are common to most global variants and which, if mutated, cause a replicative fitness loss. Our first clinical trial in low risk HIV-1-negative adults in Oxford demonstrated the principle that naturally mostly subdominant epitopes, when taken out of the context of full-length proteins/virus and delivered by potent regimens involving combinations of simian adenovirus and poxvirus modified vaccinia virus Ankara, can induce robust CD8+ T cells of broad specificities and functions capable of inhibiting in vitro HIV-1 replication. Here and for the first time, we tested this strategy in low risk HIV-1-negative adults in Africa. We showed that the vaccines were well tolerated and induced high frequencies of broadly HIVconsv-specific plurifunctional T cells, which inhibited in vitro viruses from four major clades A, B, C, and D. Because sub-Saharan Africa is globally the region most affected by HIV-1/AIDS, trial HIV-CORE 004 represents an important stage in the path toward efficacy evaluation of this highly rational and promising vaccine strategy.

Role of Different Subpopulations of CD8+ T Cells during HIV Exposure and Infection

“…In addition, the ability to maintain this response during the chronic phase is critical, as the depletion of CD8 + T cells in the SIV model showed a loss of viral control ( 69 ). Supporting the crucial role of CD8 + T cells in HIV, vaccine strategies in the SIV model promote the response of this population reducing viral replication once the challenge is established ( 70 ); in this respect, the use of some prospective vaccines tested in humans designed to trigger a strong response of this cell population showed promising results ( 71 – 73 ).…”

Early exposure to broadly neutralizing antibodies may trigger a dynamical switch from progressive disease to lasting control of SHIV infection

“…Similarly, immune checkpoint inhibitors can prevent CTL exhaustion during infection (33). CTLs can also be stimulated using vaccines (34). Our model predicts that a primed CTL population at the time of viral challenge may prevent the infection from reaching the high viremic, progressive state and drive it instead to lasting viremic control, indicating a potentially favourable outcome of prophylactic T cell vaccines.…”

HIV-1 Conserved Mosaics Delivered by Regimens with Integration-Deficient DC-Targeting Lentiviral Vector Induce Robust T Cells

“…Such regions are common to most HIV-1 variants including transmitted/founder viruses offering the potential for deployment against diverse worldwide circulating strains as well as already escaped viruses reactivated from the latent reservoirs 27 . We have pioneered virally vectored T cell vaccines designed as conserved alternating-clade consensus sequences (HIVconsv, first generation) 23 and taken them into clinical evaluation as heterologous prime-boost regimens 30, 31, 32, 33. More recently, we enhanced this conserved-region approach by replacing the consensus sequences with a bivalent mosaic design (tHIVconsvX, second generation), 34 which computationally increases as much as possible the match of candidate vaccines to the currently worldwide circulating HIV-1 variants for maximum effector efficacy 34, 35, 36, 37, 38.…”

“…We have demonstrated high immunogenicity of these heterologous prime-boost regimens in both healthy and HIV-1-positive adults 31, 33. Both adenoviruses and poxviruses prime T cells in a high-inflammatory environment, which results in a brisk expansion of polyfunctional effector T cells, but may lead to suboptimal induction of boostable central memory T cell populations, which are important for long-term protection 41 .…”