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.
Highlights
Long-term control of human immunodeficiency virus type 1 (HIV-1) infection by vaccine-induced immune responses is a widely sought after, but currently unachievable, goal of HIV cure research
While it has been clearly established that CD8+ T-cell responses against peptides of HIV-1 capsid proteins encoded by Gag (Gag proteins) can control HIV-1 replication [1,2,3], especially in HIV controllers, who control HIV-1 replication without antiretroviral therapy (ART) [4], evasion of CD8+ T-cell responses occurs in most individuals
It has been shown that infusions of broadly neutralizing human monoclonal antibodies to HIV-1 envelope (Env) antigens are capable of suppressing HIV-1 replication [7,8,9], accelerating the elimination of HIV-1-infected CD4+ T cells [10] and enhancing production of antibodies that neutralize HIV-1 [11]
Summary
Long-term control of human immunodeficiency virus type 1 (HIV-1) infection by vaccine-induced immune responses is a widely sought after, but currently unachievable, goal of HIV cure research. Studies in macaques with simian immunodeficiency virus (SIV) infection have shown that infusions of naturally occurring acute phase IgG antibodies to SIV Env antigens enhanced SIV-specific CD8+ T-cell responses by increasing virus uptake in antigen-presenting cells (APCs) [12]. Based on these observations, there is currently guarded optimism that vaccine-induced HIV-1-specific antibody responses might contribute to long-term control, and possibly eradication, of chronic HIV-1 infection [13, 14]. We discuss the characteristics of HIV-1-specific antibody responses that are likely to be required for long-term control of HIV-1 infection and in doing so, look beyond the “neutralizing/ non-neutralizing antibody” paradigm as well as consider the effects of HIV-induced immunopathology and ART on those antibody responses
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