The few antibodies that can potently neutralize human immunodeficiency virus type 1 (HIV-1) recognize the limited number of envelope glycoprotein epitopes exposed on infectious virions. These native envelope glycoprotein complexes comprise three gp120 subunits noncovalently and weakly associated with three gp41 moieties. The individual subunits induce neutralizing antibodies inefficiently but raise many nonneutralizing antibodies. Consequently, recombinant envelope glycoproteins do not elicit strong antiviral antibody responses, particularly against primary HIV-1 isolates. To try to develop recombinant proteins that are better antigenic mimics of the native envelope glycoprotein complex, we have introduced a disulfide bond between the C-terminal region of gp120 and the immunodominant segment of the gp41 ectodomain. The resulting gp140 protein is processed efficiently, producing a properly folded envelope glycoprotein complex. The association of gp120 with gp41 is now stabilized by the supplementary intermolecular disulfide bond, which forms with approximately 50% efficiency. The gp140 protein has antigenic properties which resemble those of the virionassociated complex. This type of gp140 protein may be worth evaluating for immunogenicity as a component of a multivalent HIV-1 vaccine.

We studied how combination antiviral therapy affects B cell abnormalities associated with HIV-1 infection, namely elevated circulating immunoglobulin (Ig)G antibody-secreting cell (ASC) frequencies and hypergammaglobulinemia. Within a few weeks of starting antiviral therapy, there is a marked decline in IgG-ASC frequency in both acutely and chronically infected people, whereas the hypergammaglobulinemia often present during chronic infection is more gradually resolved. These reductions are sustained while HIV-1 replication is suppressed. HIV-1 antigen–specific B cell responses are also affected by therapy, manifested by a rapid decline in circulating gp120-specific ASCs. Anti-gp120 titers slowly decrease in chronically infected individuals and usually fail to mature in acutely infected individuals who were promptly treated with antiretroviral therapy. Long-term nonprogressors have high titer antibody responses to HIV-1 antigens, but no detectable gp120-specific IgG-ASC, and normal (or subnormal) levels of total circulating IgG-ASC. Overall, we conclude that HIV-1 infection drives B cell hyperactivity, and that this polyclonal activation is rapidly responsive to decreases in viral replication caused by combination antiviral therapy.

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The effect on humoral immune responses of highly active antiretroviral therapy (HAART) commenced during primary or chronic human immunodeficiency virus type 1 (HIV-1) infection was investigated. HAART inhibited the development of anti-gp120 antibodies when initiated during primary infection and could sometimes reduce antibody titers in patients treated within 2 years of HIV-1 infection. Conversely, antibody responses in patients infected for several years were less sensitive to HAART. Administering HAART during primary infection usually did not substantially affect the development of weak neutralizing antibody responses against autologous virus. However, 2 patients treated very early after infection did not develop neutralizing responses. In contrast, 3 of 4 patients intermittently adherent to therapy developed autologous neutralizing antibodies of unusually high titer, largely coincident with brief viremic periods. The induction of strong neutralizing antibody responses during primary HIV-1 infection might require the suppression of virus replication by HAART, to allow for the recovery of immune competency, followed by exposure to native envelope glycoproteins.

Antibody responses are often considered to play only a limited role in controlling viremia during chronic infections with human or simian immunodeficiency virus (SIV). We investigated this by determining the effect of passively infused antibody on plasma viremia in infected rhesus macaques. The emphasis of the study was to understand the mechanism(s) underlying any observed effects. We infused serum immunoglobulins (SIVIG) purified from SIV(mac)251-infected macaques into other SIV(mac)251-infected macaques. The rapid progressor recipients had high viral loads but negligible titers of antibodies to SIV. Thus, we could significantly increase antibody titers with exogenous SIVIG. Despite restoring anti-SIV titers to levels typical of macaques with a normal disease course, SIVIG had only a modest effect on plasma SIV RNA and cell-associated viral load; the maximum, transient, reduction was threefold. The decrease in plasma RNA commenced within 1-2 h of SIVIG infusion, the nadir was at 12 h, and then a rebound occurred. A two- to threefold drop in cell-associated viral RNA was simultaneous with the decrease in plasma RNA. The kinetics of the viremia changes are inconsistent with neutralization of new cycles of infection. More likely, perhaps unexpectedly, is that infused antibodies killed SIV-infected cells, via an effector mechanism such as antibody-dependent cellular cytotoxicity.