Contribution of the HIV-1 Envelope Glycoprotein to AIDS Pathogenesis and Clinical Progression

Abstract

In the absence of antiviral therapy, HIV-1 infection progresses to a wide spectrum of clinical manifestations that are the result of an entangled contribution of host, immune and viral factors. The contribution of these factors is not completely established. Several investigations have described the involvement of the immune system in the viral control. In addition, distinct HLA-B alleles, HLA-B27, -B57-58, were associated with infection control. The combination of these elements and antiviral host restriction factors results in different clinical outcomes. The role of the viral proteins in HIV-1 infection has been, however, less investigated. We will review contributions dedicated to the pathogenesis of HIV-1 infection focusing on studies identifying the function of the viral envelope glycoprotein (Env) in the clinical progression because of its essential role in the initial events of the virus life-cycle. Some analysis showed that inefficient viral Envs were dominant in non-progressor individuals. These poorly-functional viral proteins resulted in lower cellular activation, viral replication and minor viral loads. This limited viral antigenic production allows a better immune response and a lower immune exhaustion. Thus, the properties of HIV-1 Env are significant in the clinical outcome of the HIV-1 infection and AIDS pathogenesis.

HIV Infection: Shaping the Complex, Dynamic, and Interconnected Network of the Cytoskeleton

“…It is important to note that efficient HIV-1 Envs to regulate the cytoskeleton during the first virus-cell contacts are also involved in cytotoxic events, such as apoptotic syncytia formation and late autophagy that eliminate bystander cells [70,327]. Therefore, the efficiency and extension of the first HIV-1 Env signals could condition the progression rate of the infection, virus variability, and associated pathogenesis, which may be related to the natural control of the infection and disease in LTNP individuals (i.e., viremic LTNPs or ECs) [56,165,328].…”

“…All these fine-tuned regulated mechanisms are essential to restrict HIV-1 early infection when HIV-1 Envs are deficient to reorganize the cytoskeleton to create a permissive cell state, as in the case of HIV-1 virus of LTNP-EC individuals [71,74,163,165]. In contrast, HIV-1 Envs from viremic and progressing HIV-1 patients productively modulate the actin cytoskeleton, their associated factors, and cell structures, and stabilize acetylated MTs, overcoming the endogenous HDAC6/TDP-43 antiviral axis to fuse, enter, and infect permissive cells [70,71,74,163,165].…”

“…All these fine-tuned regulated mechanisms are essential to restrict HIV-1 early infection when HIV-1 Envs are deficient to reorganize the cytoskeleton to create a permissive cell state, as in the case of HIV-1 virus of LTNP-EC individuals [71,74,163,165]. In contrast, HIV-1 Envs from viremic and progressing HIV-1 patients productively modulate the actin cytoskeleton, their associated factors, and cell structures, and stabilize acetylated MTs, overcoming the endogenous HDAC6/TDP-43 antiviral axis to fuse, enter, and infect permissive cells [70,71,74,163,165]. Therefore, determining the exact role of each actin/tubulin-associated protein involved in virus-triggered signaling and cell structures could help to explain the mechanism underlying HIV-1 infection, latency, and reservoir stabilization, as well as virus persistence and pathogenesis, therefore helping to understand HIV-1 patients' clinical outcomes [74].…”

“…The tubulin cytoskeleton is a key component of the cellular scaffold that HIV-1 modulates to accomplish pore fusion formation and infection. In the regulation of MT dynamics during HIV-1 early infection, the acetylation-deacetylation balance is known to be decisive and carried out by histone deacetylase 6 (HDAC6) [71,74,75,[163][164][165][166][167][168], an enzyme mainly located in the cytoplasm that regulates the deacetylation of the α-tubulin subunit in MTs [168][169][170][171][172]. The acetylation of the α-tubulin subunit at the Lys 40 residue, which is located in the inner or luminal part of the MTs [173][174][175], could be considered a posttransductional modification (PTM) marker for MT stabilization [172,174,[176][177][178][179][180][181][182][183][184][185].…”

“…The acetylation of the α-tubulin subunit at the Lys 40 residue, which is located in the inner or luminal part of the MTs [173][174][175], could be considered a posttransductional modification (PTM) marker for MT stabilization [172,174,[176][177][178][179][180][181][182][183][184][185]. Notably, it has been observed that the specific binding of the gp120 protein of the HIV-1 Env complex to CD4 at the cell surface of permissive cells increased the level of acetylation of MTs in the α-tubulin subunit [56,70,71,[163][164][165]. In fact, overexpression of deacetylase-active HDAC6 inhibited the α-tubulin acetylation of MTs by HIV-1, preventing HIV-1 Env-mediated membrane fusion and infection without affecting the expression and distribution of HIV-1 receptors (i.e., CD4, CCR5, and CXCR4), while the knockdown of HDAC6 expression or inhibition of its tubulin-deacetylase activity strongly enhanced HIV-1 Env-mediated cell-to-cell fusion (syncytia formation (virus-mediated fused giant multinucleated cells)) and HIV-1 infection of primary CD4+ T cells [164] (Figure 3).…”