What Immune Responses will be Required for an Effective AIDS Vaccine?

A fully preventive HIV vaccine would almost certainly require the induction of broadly cross-reactive and highly potent neutralizing antibodies, which would have to prevent the infection of cells and the establishment of latent infection. There is widespread agreement that this is not likely to occur, for the reasons outlined below. Indeed, most – if not all – vaccines currently in use do not achieve this level of protection. This reality has directed the field toward vaccine strategies that would prevent disease progression rather than prevent infection – which, at least in theory, would cause the epidemic to contract – if the viral load could be kept low enough to limit both disease progression and transmission.

The challenges to this direction for vaccine development are compounded by the fact that we still lack an understanding of the correlates of immune protection, despite an intricate understanding of the molecular biology of the virus (Figure 1). Despite marked differences in disease outcome followig infection, we lack a fundamental understanding of the mechanisms that account for these differences.

Figure 1. The HIV-1 genome. There are nine coding regions, in three different reading frames. gag is the main structural protein, pol encodes the replicative functions, and env encodes the heavily glycosylated outer envelope. The regulatory proteins include vif, vpr, vpr, rev, tat, and nef. LTR, long terminal repeat.

There is a growing body of data indicating that adaptive host immune responses play a role, but the key elements of protective immunity that would have to be induced by a vaccine are not known. What is known is that some persons are able to maintain successful control of HIV viremia for 30 years or more without therapy. This, in turn, provides some level of optimism that a vaccine might be able to result in a similar equilibrium with durable control of HIV, even if a totally preventive vaccine is not possible (Deeks, 2007).

In contrast, others progress from acute infection to AIDS within six months (Markowitz, 2005). Whilst the factors that account for these dramatic differences in outcome remain elusive, a growing body of data is beginning to shed light on the rational inductionof specific armsof the immune response for HIVvaccine design (Figure 2).

1. Cytotoxic T Lymphocytes

Following acute HIV-1 infection, the resolution of acute-phase plasma viremia to a semi steady-state level, or set-point, coincides with the activation and expansion of HIV-1- specific cytotoxic T lymphocytes (CTL), suggesting that virus-specific CD8 + T-cells may be responsible for reducing the levels of virus at this stage of infection. Direct evidence for the role of CD8 + T-cells in mediating the decline in viremia during acute HIV infection has come from studies of the simian immunodeficiency virus (SIV)-macaque model. Here, the administration of CD8-specific monoclonal antibodies s(MAbs) resulted in a transient depletion of CD8 + cells in both the peripheral blood and lymphoid tissues.

When administered during primary chimeric simian/HIV infections, the CD8 MAb caused marked elevations of plasma and cell-associated virus levels in both the peripheral blood and lymphoid tissues, and led to a prolonged depletion of CD4 + cells. Eliminating CD8 + lymphocytes from monkeys during chronic SIV infection resulted in a rapid and marked increase in viremia that was again suppressed coincident with the reappearance of SIV-specific CD8 + T-cel l s.

These results confirm the importance of cell-mediated immunity in controlling AIDS virus infection, and support the exploration of vaccination approaches for preventing infection that will elicit these immune responses.

Figure 2. Immune responses to HIV. The B cells produce neutralizing antibodies, which are highly type-specific and poorly recognize diverse isolates, even those that arise within a single person due to reverse-transcriptase-induced errors in replication. The cytotoxic T cells (CTL) target virus-infected cells through recognition of viral proteins presented at the cell surface associated with HLA class I molecules, and deliver a lethal hit to the infected cell, ideally before progeny viruses are produced. Despite these responses, progression ensues in most persons. T helper (Th) cells, which express CD4 and CCR5, are the central orchestrator of effective cellular immunity, but are infected in large numbers in acute infection and never fully recover; they progressively decline over time until a CD4 count of 200 is reached, which defines AIDS. Natural killer (NK) cells target virus infected cells without requiring prior exposure; emerging data suggest that these may be important in HIV control.

An emerging body of data suggests that it is not just the magnitude but rather the specificity of the CTL response that may be critical for immune containment. Numerous population studies have determined that neither the total breadth nor the total magnitude of HIV-specific CD8 + T-cell responses correlate with the ability of an individual to control HIV-1, which suggests that selected epitopespecific CD8 + T-cell responses play a relevant role.

Large population studies conducted in South Africa have defined that a preferential targeting of Gag is associated with a lower viral load, while more recent data have indicated that the breath of the Gag-specific response is negatively correlated with the viral load in persons with chronic infection. In contrast, broad Env-specific CD8 + T-cell responses are associated with a high viral load. To some extent this may reflect differences in the quality of these responses, or in the relative efficacy of different responses to recognize and kill infected cells before progeny viruses are produced.

The limited ability of these responses to provide durable containment may also be due to escape mutations emerging within targeted CD8 + T-cell epitopes, which arise during primary and chronic HIV-1 and SIV infection, and demonstrates significant CD8 + T-cell pressure on these regions of the virus and impacts temporally on disease progression. In addition, functional impairment or exhaustion of these responses over time in the setting of chronic viral stimulation may play a role.

The inhibitory receptor programmed death 1 (PD-1; also known as PDCD1), a negative regulator of activated Tcells, is markedly upregulated on the surface of HIV-specific CD8 + T-cells, the expression correlating with impaired HIV-specific CD8 + T-cell function as well as with predictors of disease progression – positively with plasma viral load, and inversely with the CD4 + T-cell count. In contrast, the inhibitory immunoregulatory receptor CTLA-4 is selectively upregulated in HIV-specific CD4 + T-cells, but not CD8 + T-cells, in all categories of HIV-infected subjects, except for a rare subset of individuals who are able to control viremia in the absence of antiretroviral therapy.

One of the strongest arguments in favor of a role for CTLs in the outcome of HIV infection is the association between certain HLA class I alleles and improved outcome. Among these are the so-called protective alleles, the strongest of which include B*5701, B*5801, B51, and B*2705. These B alleles have in common that they are associated with strong immune responses to the Gag protein, and in some cases are associated with mutations that impair viral fitness.

Other HLA alleles, such as HLA B35, are associated with a worse outcome, although an understanding of the mechanism of this association remains obscure. One concern raised by these observations is that there may be genetic limitations to the efficacy of a particular vaccine candidate, in that it may be more immunogenic in certain HLA backgrounds, and may have limited immunogenicity in others. However, this concern remains unsubstantiated.

2. Neutralizing Antibodies

Following the identification of HIV as the causative agent of AIDS, it was predicted that a vaccine inducing neutralizing antibodies and thereby preventing infection would rapidly be available. Yet, a quarter of a century later an effective preventive HIV vaccine still eludes us. Neutralizing antibodies are induced by HIV, but fail to control viremia. Despite a pronounced antibody response to the viral envelope proteins, only a small fraction of these antibodies have neutralizing activity.

This is partly due to the fact that the HIV-1 Env glycoprotein is a trimer on the virion surface with extensive Nlinked glycosylation that effectively shields many conserved epitopes from antibody recognition. Key conserved regions, such as the binding site of the chemokine coreceptor, are only formed after Env binds its cellular receptor CD4 and undergoes an extensive conformational change. The broadly reactive MAbb12 binds to the CD4binding site, suggesting that this region of Env may represent a critical point of vulnerability that is potentially amenable to neutralization, although the CD4-binding site is recessed and only partially accessible to antibody binding.

The membrane-proximal external region (MPER) of gp41 is another conserved region, which represents the target of the broadly reactive MAbs 2F5 and 4E10. However, MPER-specific neutralizing antibodies may be difficult to elicit by vaccination for multiple reasons, including tolerance control and immunoregulation, sequestration of the epitopes in the lipid membrane, exposure of the epitopes only transiently during viral entry, or possibly a combination of multiple factors.

HIV infection induces neutralizing antibodies directed against three major determinants: (i) the highly variable V3 loop; (ii) the CD4 binding domain; and (iii) the more conserved gp41 transmembrane protein. So far, most of the evidence suggests that these responses play only a minor role in immune containment in chronic infection as the antibody responses to autologous virus are typically weak. This applies also for persons who are able to control HIV infection without antiviral therapy. Furthermore, neutralization escape has been observed even in persons who persistently control viremia.

The presumably minor role of antibodies in viral control is supported by a study in which B cells were depleted with anti-CD20 antibody in an acute infection primate model, and showed little impact on viral control. This intervention led to the delayed emergence of neutralizing antibodies and no change in early viral kinetics. Despite the lack of protection, longitudinal studies of autologous neutralizing antibody responses indicate that the viral inhibitory capacity of these responses can be of sufficient magnitude to completely replace circulating neutralization-sensitive virus with successive populations of neutralization-resistant virus. 

It has even been shown that neutralizing antibody escape can exceed the rate of change observed with potent anti-HIV-1 drug selection pressure. Nevertheless, despite a gradual broadening of the neutralizing antibody response, it does not become sufficiently broad to neutralize the next population of virus to arise. Different means by which the virus evades antibody pressure have been proposed, including an evolving glycan shield and resultant steric hindrance. Even so, these studies provide evidence that the neutralizing antibody responses are strong enough to drive immune escape, and also demonstrate how quickly immune escape from neutralizing antibodies can occur.

3. CD4 + T Helper Cells

One of the central immunological defects in most individuals with HIV-1 infection is a weak to absent HIV-1-specific CD4 + T-helper cell proliferative response, although when present, HIV-1-specific T- helper cell responses have been correlated with a decreased virus load. Indeed, HIV appears to preferentially infect HIVspecific CD4 + T-cells. It is likely that the mechanism behind this association between CD4 + help and disease outcome is due to the effect of these cells on CTL function.

This has been well established in murine models of chronic viral infections, in which durable control by CTL is dependent upon the persistence of virus-specific T helper cells. Several detailed studies have demonstrated that while the primary expansion of antiviral CD8 + T-cells can occur independently of CD4 + T-cell help, memory CD8 + T-cell numbers and secondary responses to bacterial or viral challenge are decreased over time in CD4 + T-cell-deficient animal models. It has been shown that CD4 + help is particularly required for the long-term survival of memory CD8 + T-cells. In the absence of CD4 + T-cells, memory CD8 + T-cells become functionally impaired and decrease in quantity over time.

4. Natural Killer Cells

Although natural killer (NK) cells have traditionally not been considered as a component of a vaccine approach, emerging data suggest that these cells may be critical. On the one hand, NK cells respond to Toll-like receptor (TLR) ligands and help to create the proper milieu for immune induction, whereas on the other hand, recent data suggest that at least some NK cell subsets can be endowed with memory properties, allowing for a more rapid expansion on subsequent encounters. This recent discovery will no doubt influence future research directions in the HIV field.

Source :      -   Aids and Tuberculosis : A Deadly Liaison – (Books)

                        Edited by Stefan H. E. Kaufmann and Bruce D. Walker