Episode 322: HIV Cure revisited part 2 Immunotherapeutic aspects.
As you have noticed in the first part, the reservoir has been eliminated in only three PLWH until now, but that required a total destruction of their own immune system and replacement by HIV-resistant hematopoetic stem cells. Drugs have been identified that could either reactivate the reservoir or bring it into deep latency in cell culture, but there is no evidence that this is also feasible in a living person. Genetic therapy, using the CRSIPR -Cas system, could also be used to disrupt replication-competent proviral DNA, disrupt essential host co-factors (such as CCR5), or activate host restriction factors (e.g. APOBEC 3G). These are all very early in development and clinical trials have either not yet provided convincing results (as with some latency-reversal agants) or have not been done yet at all.
There are major unanswered questions with regard to penetration of drugs or viral vectors into “reservoir sanctuaries” (such as the central nervous system or the germinal centers of lymph nodes) and about safety in patients who are rather “healthy” under rather simple ART regimens. Even if these “reservoir-oriented” interventions show an acceptable benefit/risk ratio, it is expected that they will not be able to provide a sterile cure. Hence, if you wan to avoid taking pills, the immune system should keep the virus under control, just like in elite controllers.
In this episode I will first explore the progress in the use of broadly neutralizing monoclonal antibodies (BN mAbs) as a “passive” immune therapy and next turn to the possible role of improving CD8 T cells.
Par 1 Passive immunotherapy with broadly neutralizing antibodies (BN mAbs)
Ep 322-1: Barton Haynes 2017 explains how BN Abs are generated during natural infection
Model of the HIV-1 Transmission Bottleneck
Mucosal transmission reduces the genetic and phenotypic diversity of the donor HIV-1 quasispecies to only one or very few variants that seed infection in the recipient. Viruses that traverse the mucosa, but are defective or fail to initiate a productive
infection (i.e., have a basic reproductive ratio Ro of lower than 1), will be extinguished. In contrast, the mucosal bottleneck selects for viruses with a high transmission fitness with a high replicative capacity, increased infectivity, enhanced dendritic cell interaction, and greater resistance to the antiviral effects of type 1 interferons (IFNs) are likely to contribute.
Co-Evolution of HIV Transmitted-Founder Virus and Evolving Neutralizing Antibodies
The initial transmission event of sexually transmitted HIV-1 is mediated by one transmitted founder (TF) virus. The TF virus induces an initial antibody response, called the autologous neutralizing antibody, that is specific for the TF virus.
The autologous neutralizing antibody neutralizes the TF but rapidly selects virus escape mutants, which in turn induces new antibody specificities. This process is repeated throughout virus evolution such that after years of infection, a spectrum of cross-reactive neutralizing antibodies are induced, with 20% of chronically infected individuals making high levels of very broadly
reactive neutralizing antibodies.
HIV-1 Trimer and Broadly Neutralizing Antibody Binding Sites
Co-crystal structure of the HIV-1 trimer with gp120 in blue and gp41 in gray. The five areas targeted by broadly neutralizing antibodies are the CD4 binding site (orange), V1V2 glycans (red), V3 glycans (green), gp120-gp41 bridging site (purple), and the MPER (dark red). The area of insertion of the envelope trimer into the membrane is noted by the transmembrane
domain and the gp160 cytoplasmic domain is noted.
Ep 322-2: Denise Hsu Front Imm 2021: Can Broadly Neutralizing HIV-1 Antibodies Help Achieve an ART-Free Remission?
Broad neutralizing monoclonal Ab, derived from chronic progressors in clinical trials for ART replacement
Macaque studies: treatment with mAbs once very early after infection with SHIV (= simian virus with HIV envelope) → will the virus rebound after spontaneous disappearance of mAbs?
- A combination of a CD4 binding site mAb (3BNC117) + V3 glycan mAb (10-1074): a proportion of the treated animals did not show rebound
- One V3 glycan mAb (PGT121) + TLR-7 agonist as an adjuvant: significant delay or no rebound in a good proportion of the animals
Ep 322-3: Crowell Lancet HIV 2019: anti-CD4 binding site mAb VCR01 in patients ART treated from acute HIV infection.
Treatment met VCR-01, followed by analytical treatment interruption (ATI) → only 1 in 14 pt maintained viral suppression 24 weeks after ATI.
Ep 322-4: Gaebler Nature June 2022: Prolonged viral suppression and decrease in intact proviral reservoir with combined anti-HIV-1 antibody therapy
Treatment scheme with a combination of a CD4 binding site mAb (3BNC117) + V3 glycan mAb (10-1074) in subjects on viral suppressive ART for at least 7 years
a, Study design. Diamond represents time points of leukapheresis. Red and blue triangles represent 3BNC117 and 10-1074 infusions, respectively. Wk, week.
b, Levels of 3BNC117 (red) and 10-1074 (blue) in serum (n = 23 participants), as determined by TZM-bl assay18. Data are mean ± s.d. Red and blue triangles indicate 3BNC117 and 10-1074 infusions, respectively. Mean half-life (t1/2) of each bNAb is indicated in days.
Time to viral rebound after analytical treatment interruption (ATI)
-in group 1 (off ART and on mAb) versus group 2 (no mAbs and ART maintained and then stopped at week 25)
topped at week
Kaplan–Meier plots summarizing time to viral rebound for group 1 (green line) and group 2 (dotted green line)
Grey shaded area indicates time on ART for group 2 participants.
Log–rank (Mantel–Cox) test was used to determine statistical significance.
Major finding : 76% (13 out of 17) of the volunteers maintained virologic suppression for at least 20 weeks off ART
Reservoir quantification and composition.
Frequency of intact and defective proviral genomes per 106 CD4+ T cells (log normalized) as determined by Q4PCR pre-therapy and post-therapy (26 weeks) for bNAb therapy with participants who have been on ART for at least 7 years (top, circles) and baseline and follow-up (24–58 weeks) for ART-alone (bottom, squares) groups,
respectively. All participants with paired reservoirs measurements were included (bNAb therapy with at least 7 years ART n = 12, ART alone n = 10). Open symbols represent lower limit of detection (defined as half of intact proviral frequency assuming one intact proviral genome in the total number of analysed cells without target identification). Green and red horizontal bars depict mean ± s.d. of intact and defective proviral frequencies, respectively.
Major finding: selective decrease of intact proviral reservoir in pt treated with mAbs
Ep 322-5: Julia Niessl Nature June 2022: Combination anti-HIV-1 antibody therapy is associated with increased virus-specific T cell immunity.
Increased frequency of Gag-specific T cells during ATI in bNAb-treated individuals
a, Study design. b,c, Net frequency of cytokine+ CD8+ (b) or CD4+ cells (c) after Gag stimulation at weeks −2, 6/7, 12 and 18. Total cytokine+ cells include cells that express at least one cytokine and effector function upon Gag stimulation (CD107A, IFN-γ, MIP1-β and/or TNF-α for CD8+; CD40L, IFN-γ, IL-2 and/or TNF-α for CD4+). Net value was calculated by subtracting the frequency of cytokine+ cells detected in a DMSO control. Bars show median values. Symbols represent biologically independent samples from n = 9 (weeks –2, 6/7 and 12) and n = 7 (week 18) bNAb-treated individuals with suppressed viral load during ATI (week 18 sample was not available for individual 9244 and individual 9242 reinitiated ART after viral rebound at week 15). Lines connect data from the same donor. P values comparing responses at week 6/7, 12 or 18 versus baseline (week –2) were calculated using a paired two-tailed Wilcoxon test.
Conclusion: Increased HIV-1 Gag-specific CD8+ and CD4+ T cell immunity in bNAb + ATI individuals at a time when bNAbs maintained viral suppression.
- Either ART interruption in the presence of antibodies results in production of bNAb-HIV-1 immune complexes that activate antigen-presenting dendritic cells and enhance their antigen-presenting and cross-presenting capabilities to produce a vaccinal effect.
- Or nonexclusive possibility is that the augmented CD8+ T cell response is driven by increased low-grade viral replication after stop ART and antigen availability in tissues that we have not been able to assay during overt viremia suppression by bNAbs.
Whether the increased T cell responses are sufficient to help control infection remains to be determined.
Very similar findings in macaques with more direct evidence of “vaccinal effect” i.e. activation of viral-suppressive CD8 T cells, possibly as a consequence of cross-presentation of immune complexes (virus + bNAb) by dendritic cells.
Ep322-6: Nishimura Nature 2017: Combo bNAb induce long-lasting SHIV suppression in macaques, mediated by CD8+ T cells.
Control of SHIVAD8-EO replication by a 2-week course of combination bNAb therapy.
Six macaques (colored symbols were inoculated intrarectally with 1,000 TCID50 of SHIVAD8-EO and were treated with 10-1074 plus 3BNC117 (10 mg kg−1 of each) mAbs on days 3, 10, and 17 after infection. Grey curves denote replication profiles of six similarly inoculated but untreated animals.
Depletion of CD8+ T cells in controller macaques results in the rapid induction of plasma viraemia.
a–f,Plasma SHIVAD8-EO levels before and after administration of anti-CD8 depleting mAbs to six controller monkeys. Black arrows in each panel indicate the time of infusion of the anti-CD8α depleting mAb MT807R1. Red arrows in
a–c indicate infusion of the anti-CD8β depleting mAb CD8b255R1 to controller macaques MVJ, DEMR, and DEWL.
Presumed mechanism: Dendritic cell uptake of immune complex NeutAb-HIV → efficient activation of CD8+ T cells
Part 2 Therapeutic vaccination aimed to induce CD8 T cells
Ep 322-7: Collins Nat Rev Immunology 2020 CD8+ T cells in HIV control, cure and prevention
CD8+ T cell function and phenotype are modulated by the magnitude and duration of in vivo HIV antigen exposure
Elite controllers (EC) are characterized by high proliferative function of CD8 T cells
In viral controllers (VC) ex vivo killing of HIV+ CD4 T cells is maximal
The interferon production (measured in ELISPOT) rather increases towards chronic progressors (CP), hence is certainly not a correlate of protection
EC (and VC) keep the HIV under control, hence the number of escape mutations is low, but it is high in CP.
CD8+ T cell function and specificity differentiate HIV controllers and progressors.
Diagram representing CD8+ T cell interactions with infected cells in HIV controllers (top) and progressors (bottom).
HIV controller CD8+ T cells recognize structurally constrained (conserved) HIV peptides presented via MHC class I (pMHC- I) on infected cells via T cell receptors (TCRs), inducing proliferation and perforin/granzyme- mediated cytolysis of infected cells. Mutation of HIV epitopes presented via MHC- I in HIV progressors promotes escape from recognition by functional CD8+
T cells, and dysfunctional CD8+ T cells recognize non-escaped viral epitopes through TCR–pMHC- I interactions
and secrete interferon- γ (IFNγ) but fail to proliferate or kill infected cells due to inhibitory receptor–ligand interactions,
such as PD1 and PDL1. Infected cells that evade killing via escape and/or exhaustion spread infection and promote
further immune dysregulation in progressors.
HIV- specific CD8+ T cell responses in natural infection as well as following therapeutic and preventive vaccination.
Natural HIV infection Therapeutic vaccination Preventive vaccination
Diagram representing relative HIV viral load (VL , green), relative total CD4+ T cell count (CD4, violet), and relative natural (nCD8) or vaccine-induced (vCD8) HIV- specific CD8+ T cell responses over time.
In natural HIV infection (top panel), incomplete natural CD8+ T cell- mediated control of VL eventually leads to disease progression, marked by CD4+ T cell decline and uncontrolled VLs.
Therapeutic vaccines that elicit effective vaccine- induced CD8+ T cell- mediated control of viraemia aim to protect against disease progression, lower VLs to below the transmission threshold and contain and reduce the residual HIV reservoir in the absence of antiretroviral therapy.
Preventive CD8+ T cell- mediated vaccines aim to induce a rapid memory- recall, vaccine- induced CD8+ T cell
response and clear the first infected cells to prevent reservoir establishment as well as to control and ideally clear residual infected cells.
In fact, since 2019 only a few new papers on therapeutic vaccination have appeared. I discuss just one to illustrate the rather limited progress in the field.
Ep 322-8: Yovaninna Alarcón-Soto Nat Med 2021 HIVACAT T-cell immunogen (HTI) in early treated HIV-1 infection
This immunogen is designed to include T cell epitopes associated with low viral load in untreated subjects.
Complex set-up: heterologous DNA prime with 2 viral vector boosts
- HTI 3X as DNA plasmid, 3 X in MVA (modified vaccina Ankara) AND 2 X as Chadox (Chimp Adeno) vector,
- followed by analytical treatment interruption (ATI) during 24 weeks
- resumption of antivirals (ARV)
Clear increase of immune responses and viral inhibition in vaccine recipients versus placebo
Moderate delay in viral rebound in vaccinees vs placebo
Heterologous prime-boost regimen of HTI vaccines in early ART-treated individualswith HIV infection
- was safe and immunogenic.
- showed a potential signal for improved post-rebound viral control after ART discontinuation in a subset of individuals who did not already possess a beneficial HLA genotype;
This requires validation in future studies.
SOME GENERAL CONCLUSIONS
Unfortunately, after 4 years that I did not follow it, I have to conclude that, despite some interesting new papers and review, the field of HIV Cure has not progressed spectacularly.
- There are many potential drugs and possible genetic manipulations that could influence the viral reservoir, but, with the present state of the art, it seems impossible to really eradicate or permanently silence HIV from infected individuals, unless the complete immune system is destroyed and replaced by an HIV-resistant system, as was done in the three “cured” patients
- Combinations of broad neutralizing antibodies and some therapeutic vaccines could delay viral rebound. It is clear that the immune system can be improved, but not sufficiently to permanently suppress viral replication to undetectable levels.
- In the meantime, we also know that even elite controllers, with undetectable viral load, may suffer from long-term adverse health consequences. Therefore partial success in cure strategies is not enough.
- On the other hand, ART is being further simplified with long-acting drugs.
Cure research remains scientifically interesting, as it improves our knowledge on HIV pathogenesis, but a complete cure from HIV is not within immediate reach.
I will be off during a few days, visiting our granddaughters in Geneva.
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