A critical question for HIV vaccine development Which antibo(3)

A critical question for HIV vaccine development Which antibodies to induce.

an antigen that stimulates an appropriate germ-line immunoglobulin gene and then boost with a series of immunogens recapitulating the evolu-tion of the virus as it escapes from Ab-mediated immune pressure,thus steering B cell differen-tiation through mutational steps that are required in vivo for the production of bnAbs.Targeting of more than one epitope will likely be needed,given the mutation rate of HIV.Notably,there are currently no data demonstrating that this approach is feasible.

Simultaneously,there is a growing literature describing rationally designed vaccines that in-duce protective conventional Abs.This approach depends on identification of the epitopes recognized by protective conventional monoclonal Abs (mAbs)and the subsequent use of structural,bioinfor-matics,and molecular methods to design immu-nogens that will induce polyclonal Abs similar to the originally identified protective mAbs.This approach has led to the design of vaccine candi-dates against several pathogens (17,18),and epitope-scaffold immunogens have already been shown to successfully induce conventional cross-clade neutralizing Abs against HIV (19–21).Ini-tially,conventional Abs were shown to be protective against HIV by demonstrating that chimpanzees could be protected by infusing the challenged animals with immunoglobulin G (IgG)from an HIV-infected chimpanzee (22).Subsequently,hu-man mAbs,representing conventional Abs made by most chronically infected individuals,were shown to neutralize multiple lab-adapted and/or primary isolates in vitro (23–29),and two of these mAbs,specific for the third variable region (V3)of the HIV gp120envelope glycoprotein,provided protection against heterologous HIV strains in relevant animal models (30,31).More than 90%of chronically infected HIV+subjects make sim-ilar V3Abs (32).

Unlike in many viral infections,HIV-infected individuals can become “superinfected ”with a second HIV strain.This might suggest that Abs that develop in HIV patients are not protective.However,several studies suggest that Abs made in HIV-infected individuals do affect the rate of superinfection.For instance,superinfected indi-viduals had lower levels of cross-protective and autologous neutralizing Abs than the nonsuper-infected case-controls (33,34).Although some studies are contradictory to these (35,36),and other data suggest that cytotoxic T lymphocytes are capable of imposing selective pressure on HIV (37),results from a recent adequately powered study demonstrated that a first HIV infection re-duces the risk of a subsequent infection by ~50%in high-risk Kenyan women (38).Additional evi-dence for the protective role of Abs comes from studies of maternal-fetal transmission.Although not replicated universally,several studies showed lower transmission rates from infected pregnant women with high Ab titers or with high-affinity/avidity Abs to portions of the HIV-1envelope glycoproteins (39).

These studies complement those showing that Abs commonly exert strong and rapid immune pressure on viruses in vivo .For instance,when

serial plasma samples from patients with primary HIV infection were examined for neutralizing activity against autologous viruses,the plasma virus continually and rapidly evolved to escape neutralization (40,41).Moreover,as early as 2weeks after seroconversion,very low titers of neutralizing Abs select for escape viruses in acutely infected patients (42).These studies in-dicate that Abs produced in the majority of pa-tients can eliminate viruses bearing cognate antigenic determinants.If a vaccine were to produce a similar conventional polyclonal Ab response in uninfected individuals,it may be possible that most or all of an incoming virus inoculum could be eliminated by these Abs.Additional support for the role of Abs in pro-tection comes from the RV144clinical vaccine trial in which subjects received four doses of a recombinant HIV –avian pox virus and two doses of gp120proteins from two different HIV sub-types.An estimated vaccine efficacy of 31%was noted at 3years of follow-up (43)and 60%at 1year after immunization (44).Higher levels of IgG Abs specific for epitopes in the second variable loop (V2)and V3region of gp120—Abs commonly found in HIV-infected individuals (32,45,46)—were significantly associated with the reduced rate of infection (47–49).Several independent studies have confirmed that Abs to V2and V3correlated with the reduced rate of infection noted in RV144vaccine recipients (48,50–52).

There are,therefore,many lines of evidence that indicate that despite their reduced potency and breadth as compared to bnAbs,conventional Abs made by the majority of HIV-infected indi-viduals may be able to prevent infection.More-over,conventional Abs display additive and synergistic activity (53–56)that may explain the ability of polyclonal conventional Ab responses to reduce the risk of HIV-1infection.

At this point,there are no definitive data dem-onstrating that either vaccine-induced conven-tional or exceptional Abs will result in protection from HIV infection in humans.The clearest in-dication comes from the data emanating from the RV144vaccine trial (47,48,50–52),but,strong as these data are,there is as yet no absolute proof of the hypothesis that conventional Abs are pro-tective in humans.Nor do such data exist for bnAbs.In addition,it is possible that vaccine-induced conventional Abs will need to be induced at higher titers than bnAbs and may not protect against as many strains.The data do suggest that conventional Abs may be more feasible to induce,whereas bnAbs may ultimately be more effective.Therefore,both approaches have their strengths and weaknesses,and both must be pursued with equal vigor.

REFERENCES AND NOTES

1.M.D.Simek et al .,J.Virol.83,7337–7348(2009).

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