HIV-1-specific cross-reactive humoral immunity is assumed to be directed against relatively conserved regions on the viral envelope. As a consequence, HIV-1 may be unable to rapidly escape from cross-reactive NAb pressure, suggesting that a broad and potent humoral immune response may influence the clinical course of infection. However, we have recently demonstrated that the prevalence of cross-reactive neutralizing activity in serum is similar among HIV-infected individuals with a progressive disease course and LTNP (37
). This absent correlation between disease course and cross-reactive neutralizing activity in serum could either point to fading humoral immunity in the progressive course of infection or to viral escape from antibody pressure, as has been shown to occur in response to type-specific neutralizing humoral immunity (8
In the longitudinal analysis performed in our present study, cross-reactive neutralizing humoral immunity was preserved in both LTNP and progressors, even after the moment of AIDS diagnosis in those individuals who ultimately progressed to AIDS. In contrast, autologous neutralizing activity was only observed against viruses that were isolated early in infection. Moreover, this limited autologous neutralizing activity against early viruses was lost after AIDS diagnosis. These findings not only point toward a rapid selection of HIV-1 variants that resisted the neutralizing activity in serum, they also demonstrate the inability of the infected host to generate novel neutralizing antibody specificities against these escape variants.
One could argue that the apparent discrepancy between preserved cross-reactive neutralizing activity but fading autologous neutralizing activity could relate to differences in sensitivities of the assays used for their detection (13
). Cross-reactive neutralizing activity was tested against a panel of pseudoviruses in a U87-based assay, whereas autologous neutralizing activity was tested in a PBMC-based assay with replicating viruses. However, we have previously shown that the relative potency of neutralizing serum activity as detected by these two assays is comparable (37
). The different profiles of autologous versus heterologous neutralizing activity over the course of infection as observed in the present study are thus likely to reflect true differences in the development and persistence of these components of neutralizing serum activity.
We recently demonstrated that escape from type-specific autologous neutralizing activity in serum did not influence the in vitro
replication fitness of HIV-1 (7
). However, our observation that rapid escape of HIV-1 from autologous humoral immunity with cross-reactive neutralizing activity also had no impact on the viral replicative fitness was somewhat unexpected since BrNAbs are considered to target conserved epitopes which, by definition, carry crucial functions for the virus. It is tempting to speculate that replication fitness is restored by compensatory mutations that may rapidly be selected. This is currently under investigation.
Overall, the similar potency of humoral immunity, the similar dynamics of viral escape, and the absent impact of escape on the replication kinetics of viruses from both LTNP and progressors argue against a role for NAb in the clinical course of infection. In agreement, we and others have shown in comprehensive cohort analyses that the presence of cross-reactive neutralizing activity was not associated with prolonged AIDS free survival (12
). Indeed, HIV-1 cellular immunity and host genetic background seem to have a more pronounced effect on disease progression (17
Escape from autologous neutralizing humoral immunity with cross-reactive activity coincided with an increase in the length and number of PNGS of gp160 and an increase in the net charge of the V2 region. Similar changes were observed in HIV-1 variants that escaped from autologous neutralizing humoral immunity with only type-specific activity (8
). This may either suggest that the same mechanisms apply for escape from different antibody specificities or that the relevant changes for escape from cross-reactive neutralizing antibodies are masked by changes that are selected by type-specific antibodies. Positive selection pressure was mainly observed in the variable regions of the envelope protein. Interestingly, two novel highly potent cross-reactive neutralizing antibodies directed against a conformational epitope in the V2V3 region have recently been described (40
), suggesting that the variable regions can indeed be targeted by cross-reactive neutralizing antibodies.
We are currently studying the exact nature of the humoral immune response in the individuals in our study which will reveal whether the cross-reactive neutralizing activity is determined by a single high-affinity antibody or by a combination of multiple coexisting neutralizing antibodies directed at multiple distinct regions of the envelope. The results from these analyses will help to define which changes in the viral envelope are relevant for escape from cross-reactive neutralizing activity.
Taken together, our findings seem to underscore the absent role for cross-reactive neutralizing humoral immunity in the protection from disease progression due to the ability of HIV-1 to rapidly escape from this immune pressure without a loss of viral fitness. Whereas vaccine-elicited cellular immunity may be able to control viremia and thereby contribute to protection from disease progression (10
), our results support the notion that vaccine-elicited BrNAbs may only be relevant for protection from the acquisition of infection.