Neutralizing antibody responses against autologous and heterologous viruses in acute versus chronic human immunodeficiency virus (HIV) infection: evidence for a constraint on the ability of HIV to completely evade neutralizing antibody responses

Abstract

Acute human immunodeficiency virus (HIV) infection is associated with the rapid development of neutralization escape mutations. The degree to which viral evolution persists in chronic infection has not been well characterized, nor is it clear if all patients develop high-level neutralization antibody escape. We therefore measured neutralizing antibody responses against autologous and heterologous viruses in a cohort of acutely and chronically infected subjects (n = 65). Neutralizing antibody responses against both autologous virus and heterologous viruses were lower among individuals with acute infection than among those with chronic infection. Among chronically infected individuals, there was a negative correlation between the level of neutralizing antibodies against autologous virus and the level of viremia. In contrast, there was a positive correlation between the level of neutralizing antibodies against a panel of heterologous viruses and the level of viremia. Viral evolution, as defined by the presence of higher neutralizing titers directed against earlier viruses than against contemporaneous viruses, was evident for subjects with recent infection but absent for those with chronic infection. In summary, neutralizing antibody responses against contemporaneous autologous viruses are absent in early HIV infection but can be detected at low levels in chronic infection, particularly among those controlling HIV in the absence of therapy. HIV replication either directly or indirectly drives the production of increasing levels of antibodies that cross-neutralize heterologous primary isolates. Collectively, these observations indicate that although HIV continuously drives the production of neutralizing antibodies, there may be limits to the capacity of the virus to evolve continuously in response to these antibodies. These observations also suggest that the neutralizing antibody response may contribute to the long-term control of HIV in some patients while protecting against HIV superinfection in most patients.

FIG. 1.

(A) Neutralizing antibody titers against contemporaneous autologous virus for subjects with acute HIV infection (n = 19) and for subjects with chronic infection (n = 41). (B) Relationship between HIV RNA levels and the neutralizing titers against autologous virus for antiretroviral drug-untreated, chronically infected subjects. There was a negative correlation between viremia and the autologous neutralizing antibody titer (ρ = −0.40, P = 0.05). (C) Relationship between HIV RNA levels and the mean neutralizing titers against a panel of viruses obtained from other antiretroviral drug-untreated subjects with chronic infection. There was a positive correlation between viremia and the average heterologous response (ρ = 0.53, P = 0.02). For each panel, the neutralizing antibody titer is defined as the reciprocal of the dilution of plasma that produces 50% inhibition of target cell infection (higher titers signify greater levels of neutralizing activity).

FIG. 2.

Change in response to baseline autologous virus and to laboratory viruses over time in recent (A) and chronic (B) HIV disease. (A) Five acutely infected subjects initiated and later interrupted antiretroviral therapy. Viral rebound was associated with increased responses against contemporaneous virus (P = 0.04), the baseline autologous virus (P = 0.002), SF162 (P < 0.001), and NL4-3 (P < 0.001). The response to earlier autologous viruses was consistently higher than the response to autologous virus (data not shown). (B) The neutralizing responses to baseline autologous virus, SF162, and NL4-3 were measured over 1 year for 23 chronically infected subjects not modifying or initiating therapy. There was no evidence for a change over time (P of >0.30 for each virus). Changes in neutralizing antibody titers were analyzed using generalized estimating equations and assessed with nonlinear tests of trend. Median values and interquartile ranges are shown.

FIG. 3.

Change in response to autologous virus and NL4-3 after initiation of an effective antiretroviral treatment regimen. (Top) Seven antiretroviral drug-untreated subjects with chronic HIV disease initiated and responded virologically to combination antiretroviral therapy. (Middle) Neutralizing titers against autologous virus were low and did not change significantly during the first 1 to 2 years of treatment. Two subjects experienced intermittent viremia (“blips”) upon therapy; autologous responses appeared to increase concurrently with these episodes. (Bottom) In contrast, neutralizing activity against NL4-3 was high prior to therapy and decreased rapidly during treatment. HAART, highly active antiretroviral therapy. Study visit 1 refers to the visit just prior to the initiation of antiretroviral therapy. The subsequent study visits were each separated by 4 months. One subject (3022; light blue) did not have evaluable responses directed against autologous virus.