Virus-Specific Host Immune Responses

The initial phase of HIV-1 infection is characterized by high-level viremia, associated with the ability to detect the viral core protein p24 in the serum. However, soon after infection the level of viremia and p24 antigenemia rapidly decrease (see Fig. 407-6). A long period of relatively asymptomatic infection ensues, suggesting that virus-specific immune responses may play a role in limiting viral replication and thereby disease progression. With the AIDS epidemic now entering its third decade, identification of the precise protective components of anti-HIV immunity remains an elusive goal, although significant progress has been made.

Neutralizing Antibodies
HIV infection induces B lymphocytes to produce antibodies directed against viral proteins, and some of these antibodies are capable of neutralizing the virus. Antibody responses are typically observed 1 to 3 months after primary infection, although longer periods before antibody responses develop have been documented in rare instances. Neutralizing antibodies directly neutralize free virus at a stage before the virus has entered the cell and become uncoated. In a number of viral infections, neutralizing antibody induced by immunization correlates with protection from subsequent viral infection. HIV-1 infection results in the production of HIV-specific antibodies directed at a number of viral proteins, and some of these antibodies demonstrate neutralizing activity. The primary target of neutralizing antibodies is the envelope glycoprotein, in particular a loop structure within a relatively hypervariable region of the gp120 glycoprotein termed the principal neutralizing domain or V3 loop, as well as epitopes in the region involved in CD4 binding that recognize conformationally determined regions that are composed of discontinuous segments brought together in the tertiary structure of the envelope protein.

Neutralizing antibodies have been demonstrated to be present at all stages of HIV-1 infection, and although titers are generally lower in later stages of illness, attempts to correlate neutralizing antibody titers with disease progression have yielded conflicting results. Detailed studies in primary HIV-1 infection have demonstrated that antibodies capable of neutralizing the infecting strain of virus appear after clearance of the primary viremia, suggesting that other immune mechanisms may be important in the early control of viremia. In addition, it has been demonstrated that antibodies from infected persons at a given point in time tend to be poorly able to neutralize the infecting strain of virus, but much better at neutralizing laboratory strains of virus. Although a number of animal studies have shown that neutralizing antibodies can confer protection against viral challenge, this protection has been largely in highly idealized situations in which maximal titers were induced just prior to challenge and a low inoculum of virus was given intravenously. Whether induction of neutralizing antibodies alone would be able to confer protection against naturally acquired infection is not known, but it will be important for vaccine candidates to be able to induce these responses.The ability of HIV-specific neutralizing antibodies to confer protection may be impaired in part by the high degree of antigenic variation exhibited by HIV. This antigenic variation is particularly pronounced in the envelope region of the virus, and virus variants may emerge within an infected individual that are neutralization resistant.