Anti-Gag antibodies gag HIV infection and slow disease progression

In a research article published in this issue of AIDS, Chung et al.[1] demonstrate that anti-Gag-p24 antibodies of IgG1 are associated with viral control in HIV-infected individuals. More importantly, antip24 IgG1 antibodies, but not gp120-specific antibodies, predicted lower viral loads and higher CD4+ T-cell counts independently from Gag-specific CD4+ and CD8+ T-cell responses, as well as from carriage of protective HLA-B alleles. The protective antibodies mediated FcγR-mediated effector functions, that is, antibody-dependent phagocytosis (ADP) and antibody-dependent cell-mediated cytotoxicity (ADCC), and so forth. Chung et al. [1] carried out this study using archived plasma samples from 163 treatment-naïve individuals infected with clade C HIV-1 (most prevalent in the World) in a cohort established in Durban, South Africa. This is not the first time that Gag-specific antibodies have been described to play a protective role in HIV-infected individuals. There are at least two dozen reports in literature published since 1989 showing that higher concentrations of anti-Gag antibodies predict a better prognosis and their decreasing concentrations predict progression of the disease [2]; reviewed by French et al. [3]. More recently, it was demonstrated that anti-Gag antibodies of IgG2 isotype effectively discriminate between HIV controllers and noncontrollers, whereas antigp120 antibodies were less discriminatory between the two groups of HIV-infected individuals [2,3]. Anti-Gag antibodies did not receive enough attention probably because Gag is not expressed on the surface of virions or virus-infected cells. It is noteworthy that most of the known antibody-mediated effector functions, for example, virus-neutralization, ADCC, ADP and virolysis, and so forth, require expression of the target antigen on the surface of virion or virus-infected cells. Gp120/41 are, therefore, the main target of anti-HIV antibodies. Not surprisingly, they have been the main focus of researchers and have been extensively studied in HIV-infected individuals for their ability to induce virus neutralization, ADCC and ADP. The initial strategy for developing anti-AIDS vaccine was also based on virus neutralizing antibodies and use of the viral envelope proteins as immunogens [4]. Gag (Group-specific antigen) plays an essential role in the assembly and budding of virions at the plasma membrane. It is originally translated as a multidomain polyprotein that is anchored via its myristoylated N-terminus to acidic phospholipids present in the inner leaflet of the plasma membrane [5]. Inside virions, the Gag polyprotein is cleaved by viral protease into six distinct proteins and peptides, including p17 (Matrix), p24 (Capsid/Core), and p9 (Nucleocapsid), and so forth. P24 is the most abundant protein found in HIV-infected cells, as well as in the circulation of virus-infected individuals [6]. The protein is used as a surrogate marker for diagnosis of HIV infection and its progression in HIV-infected patients. Gag is a relatively conserved protein. Mutations within the protein are not tolerated well because they cost viral fitness. Numerous studies have shown that Gag-specific CD4+ and CD8+ T-cell responses protect the host from progression of HIV disease [7], and anti-Gag antibodies are considered as a surrogate marker for a strong HIV-specific CD4+ T-cell responses [8]. After failure of gp120/41-based vaccines, the strategy for developing AIDS vaccine was shifted from an antibodies-based one to a T-cell-based one. Gag formed an integral component of the vaccine regimens used for the T-cell-based strategy. Clinical trials for testing the efficacy of T-cell-based vaccines also failed to show any benefit in the vaccinated individuals [9]. Given that Gag-p24 is not expressed on the surface of virions or virus-infected cells, it would be important to investigate the effector mechanism(s) of anti-Gag antibodies. As mentioned by Chung et al. [1], Gag may be exposed to the cell surface when HIV buds from the plasma membrane, HIV-infected cell undergo apoptosis and/or cells are super-infected with the virus. In addition, it has also been shown that latently infected CD4+ T cells express Gag on their surface [10]. Although further investigations are needed to test whether antip24 antibodies can target these cells, it has been shown that their protective effect correlates with their ability to activate plasmacytoid (p)DC via their opsonophagocytic activity [11,12]. It is believed that Gag (bound with viral RNAs) exists in immune complexes in the circulation and body fluids. Whenever the complexes are endocytosed via FcyRIIa by pDC, the viral RNAs activate TLR-7 and induce the production of type I interferons (IFN-I), which activate natural killer cells and induce interferon-stimulated genes that encode molecules with antiviral functions. IFN-I is known to effectively suppress viral replication in simian immunodeficiency virus (SIV)-infected macaques [13]. Correlation of pDC-reactive opsonophagocytic anti-P24 antibodies with the control of acute and chronic viral infections has been demonstrated [2,11]. Further studies are needed to investigate whether TRIM-21 (an intracellular FcyR that binds antibodies in the cytosol, degrades bound antigens and induces inflammatory response [14]) and FcRn (neonatal FcR that recycles IgG and degrades bound antigen [15]) play any role in the protection afforded by antip24 antibodies. The results presented by Chung et al.[1] are provocative but not without limitations. They are based on correlations. It would be important to show their causal effect on disease progression in animal models or infected individuals by passive transfer. Nevertheless, they bear important implications for developing an AIDS vaccine, which is the only cost-effective way of controlling an HIV epidemic. Because of a demonstrated protective role of anti-Gag antibodies in controlling viral replication, Gag should be used as an immunogen in vaccination regimens that favor the induction of anti-Gag antibodies. Interestingly, when HIV-p24 was used to vaccinate cats against feline immunodeficiency virus (FIV) using IFN-γ as an adjuvant, it produced cross-reactive antibodies to FIV-p24 that provided 78% protection to the vaccinated cats [16]. Furthermore, the article reinforces results obtained from the only clinical trial (RV144), which has demonstrated some measure of success for an AIDS vaccine [17]. Together, they promote the concept that HIV-specific poly-functional antibodies mediating their effector functions via FcyR expressed on innate immune cells (monocytes, macrophages, dendritic cells and natural killer cells, etc.) protect humans from AIDS by slowing disease progression. It is not known whether the RV144 vaccine induced any anti-Gag antibodies in the vaccinees. In hindsight, the addition of a boost step with p24 may have stimulated antip24 antibodies in the vaccinated individuals. Acknowledgements Conflicts of interest There are no conflicts of interest.

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