Antiviral Functions of Human Immunodeficiency Virus Type 1 (HIV-1)-Specific IgG Antibodies: Effects of Antiretroviral Therapy and Implications for Therapeutic HIV-1 Vaccine Design

Abstract

Contemporary antiretroviral therapy (ART) is effective and tolerable for long periods of time but cannot eradicate human immunodeficiency virus type 1 (HIV-1) infection by either elimination of viral reservoirs or enhancement of HIV-1-specific immune responses. Boosting "protective" HIV-1-specific immune responses by active or passive immunization will therefore be necessary to control or eradicate HIV-1 infection and is currently the topic of intense investigation. Recently reported studies conducted in HIV patients and non-human primate (NHP) models of HIV-1 infection suggest that HIV-1-specific IgG antibody responses may contribute to the control of HIV-1 infection. However, production of IgG antibodies with virus neutralizing activity by vaccination remains problematic and while vaccine-induced natural killer cell-activating IgG antibodies have been shown to prevent the acquisition of HIV-1 infection, they may not be sufficient to control or eradicate established HIV-1 infection. It is, therefore, important to consider other functional characteristics of IgG antibody responses. IgG antibodies to viruses also mediate opsonophagocytic antibody responses against virions and capsids that enhance the function of phagocytic cells playing critical roles in antiviral immune responses, particularly conventional dendritic cells and plasmacytoid dendritic cells. Emerging evidence suggests that these antibody functions might contribute to the control of HIV-1 infection. In addition, IgG antibodies contribute to the intracellular degradation of viruses via binding to the cytosolic fragment crystallizable (Fc) receptor tripartite motif containing-21 (TRIM21). The functional activity of an IgG antibody response is influenced by the IgG subclass content, which affects binding to antigens and to Fcγ receptors on phagocytic cells and to TRIM21. The IgG subclass content and avidity of IgG antibodies is determined by germinal center (GC) reactions in follicles of lymphoid tissue. As HIV-1 infects cells in GCs and induces GC dysfunction, which may persist during ART, strategies for boosting HIV-1-specific IgG antibody responses should include early commencement of ART and possibly the use of particular antiretroviral drugs to optimize drug levels in lymphoid follicles. Finally, enhancing particular functions of HIV-1-specific IgG antibody responses by using adjuvants or cytokines to modulate the IgG subclass content of the antibody response might be investigated in NHP models of HIV-1 infection and during trials of therapeutic vaccines in HIV patients.

Keywords: IgG antibody function; IgG subclasses; antiretroviral therapy; fragment crystallizable receptors; human immunodeficiency virus type 1.

Figure 1

Diagrammatic representation of immune responses against viruses and the functional effects of virus-specific IgG antibodies in those responses. (A) CD8⁺ T-cell responses, which are dependent on the activity of antigen-presenting cells (APCs), (B) neutralizing antibodies, (C) natural killer (NK) cell responses, including activation by IgG antibodies, and (D) APC activity of conventional dendritic cells (cDCs) for CD8⁺ T cells and antiviral immune responses of plasmacytoid dendritic cell (pDCs), particularly production of type 1 interferons, both of which are enhanced by opsonophagocytic IgG antibody responses [modified from Tjiam et al. (18)].