Contribution of the HIV-1 Envelope Glycoprotein to AIDS: Comparison
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Please note this is a comparison between Version 1 by Agustín Valenzuela-fernández and Version 2 by Peter Tang.

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. 

  • HIV-1 Env function
  • natural control of the infection
  • elite controllers

1. Introduction

In the absence of antiretroviral therapy (ART), the hallmark of human immunodeficiency virus type 1 (HIV-1) infection is the gradual destruction of the naive and memory CD4+ T-lymphocytes and the associated immunological abnormalities leading to the acquired immunodeficiency syndrome (AIDS) [1][2][3][4][5][6][7][8][9][10][11] (Figure 1, progressors immune system damage, top box). The severity of the symptoms and viral transmission strongly correlate with the peak of viral load (VL) during primary infection and the subsequent viral set-point [12][13][14][15][16][17][18][19][20][21][22][23][24]. HIV-1 infection is characterized by a wide spectrum of disease outcomes according to the progression time of patients. Different nomenclatures have been used to name the distinct groups of HIV-1 individuals (reviewed in [25]). The typical HIV-1 infected patient, in the absence of ART, progresses to AIDS and death over a period of about 8–10 years after seroconversion [5][26][27]. Some patients, designated rapid progressor (RP), progress to AIDS within three years of primary infection [26][28][29]. On the other side, there is a small subset of HIV-1 individuals that are able to permanently control viral replication and clinical progression and might never progress or progress very slowly [5][30] (Figure 1, non-progressors immune system damage, bottom box). In general, these subjects have been infected with HIV-1 for more than ten years, maintaining high CD4+ lymphocyte numbers, undetectable VL, without clinical symptoms, and remaining therapy naïve [31]. These individuals have been defined as long-term non-progressors (LTNPs) [32][33][34][35][36], elite controllers (ECs) [30][37], slow progressors [38][39][40], HIV controllers (HICs) [41] and elite suppressors [42]. Within this set of individuals, some subgroups can be distinguished in terms of VL: viremic LTNPs or viremic controllers (vLTNPs or LTNP-VCs) with VLs between 50 and 2000 copies/mL [32], LTNPs viremic non-controllers (LTNP-NCs) with VLs above 2000 copies/mL [43], and LTNP-Elite controllers (LTNP-ECs) with undetectable viral loads (<50 copies/mL) [26]. In the LTNP-ECs subgroup, there is a natural control of the infection without any ART, maintaining undetectable HIV-1 viral loads for long periods of time (even for more than 20–30 years) and lack of clinical progression [44]. This clinical phenotype is the consequence of the necessary cooperative interaction of host, immune, and viral factors [26][30][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66] (Figure 1, non-progressors bottom box). Several investigations described the contribution of the immune system, both at the cellular and serological level, in the primary and the subsequent control of the viral infection. This control is the result of many elements and the activity of different cell types, such as CD4+ and CD8+ T cells, natural killers (NKs), dendritic cells (DCs), different types of antibodies (Abs), cell restrictions factors, human leucocyte antigens (HLAs) genotypes and/or host factors like CCR5 protective mutations [26][44][45][48][49][50][51][52][53][54][56][61][66][67][68][69][70][71][72][73], as summarized in Figure 1. In addition, HLA-B genotypes HLA-B57/B58 or -B27 [63], HLA-B*35:01 [74][75] and HLA-C [26][76][77], such as the HLA-C*03:02 1 in an African Pediatric Population [78], are linked with the control of HIV-1 infection (Figure 1, non-progressors bottom box). In some LTNP individuals [79] that harbor viruses with low replication capacity [80][81][82][83], the HIV-1 LTNP phenotype has been associated with the presence of potent and broad cytotoxic T lymphocyte (CTL) responses [66][84] (Figure 1, non-progressors bottom box) and active NK cells.
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Figure 1. Scheme summarizing the events in primary HIV-1 infection associated with the immune control and damage, in HIV-1 progressor and non-progressor phenotypes: Main immune responses and damage associated with progressors HIV-1 infected individuals (top box) and non-progressors (bottom box) clinical phenotypes. Top box, in an acute phase of the HIV-1 infection, antigen-elicited rapid responses of innate immune cells lead to the activation of natural killer (NK) cell receptors together with monocytes/macrophages and the release of inflammatory cytokines/chemokines. This HIV-1 elicited-NK cells activation leads to secretion of IFN-γ and MIP-1β to limit viral spread [85], modulate the adaptive response in an interplay with DCs [86], and shape the induction of antibodies through the elimination of follicular T cells (Tfh) [87]. Macrophages and microglia that survive after acute HIV-1 infection could become viral reservoirs [88]. High VL is associated with predominant destruction of bystander non-infected CD4+ T mediated by HIV-1 Env (reviewed in [2][89][90]), a process the researchers have previously reported to be dependent on the HIV-1 gp41-Env subunit by promoting autophagy and apoptosis [91][92][93][94][95][96]. Bottom box, some host factors, such as viral antigen-elicited CD8+ T cell response and Th1-type cytokine production [66][97][98][99], NK cell receptors [67], HLA polymorphisms [61] and CCR5 protective mutations (i.e., homo and heterozygous CCR5-Δ32 and heterozygous CCR5-Δ24 deletions/genotypes) [45][48][49][50][51][52][53][54][56] together with a limited pro-viral reservoir [68] and some restriction factors [69] have been related to a protective phenotype against HIV-1 infection. *Red and *green triangles represent how the viral infection progresses in HIV-1 infected patients of extreme different clinical phenotype: progressors (red triangle) and non-progressors (green triangle). The boxes summarized the main associated immune responses observed for the related clinical phenotype.

2. HIV-1 Envs from LTNP-EC Individuals Present Inefficient Viral Functions, Associated with the Natural Control of the Infection and the Non-Progressor Clinical Phenotype

The investigation of the HIV-1 env/Env functions was undertaken analyzing viruses from HIV-1 individuals with different clinical phenotypes: LTNP-EC, viremic non-progressor, progressor and rapid progressor (RPs) [26][44][70][71][72][73][83][100][101][102][103][104][105][106]. In the initial studies, the researchers focused on LTNP individuals infected for long periods of time (i.e., more than 10 years and with more than 25–30 years of clinical follow-up) [26][44][70][72][100][106]. The isolated viral env sequences (full-length viral env) from infected individuals were cloned into expression plasmids (Figure 2a). The viral clones were completely sequenced at the nucleotide level and submitted to phylogenetic analysis (Figure 2a). These viral Envs were then characterized by multiple phenotypic test/assays to disclose the principal properties of their viruses (Figure 2b–e). In order to do this, the researchers developed several techniques to study the functions of viral Env during the first steps of the viral cycle. This phase of the viral cycle is a complex multistage process with highly regulated steps involving many cellular molecules mobilized by the Env viral binding to CD4, CXCR4 or CCR5 receptors [107][108][109][110][111][112][113][114][115][116][117][118]. As the researchers and others described, these interactions end in the formation of a fusion pore through which the viral capsid enters the cell [102][104][119][120][121]. The efficient pore fusion formation relies on key signals triggered by Env-CD4 interaction promoting cytoskeleton modifications [102][104][119][121], such as microtubules (MTs) acetylation in the α-tubulin subunit [121], F-actin severing, and capping reorganization [102][104]. A deficiency in these HIV-1-Env-mediated signals leads to a defect in the early steps of viral infection and replication [102][104][119][120][122][123][124], which ends in a limited viral replication.
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Figure 2. Schemes of the experimental procedures followed to characterize primary HIV-1 envs/Envs from HIV-1 infected patients: The researchers studied viral Envs of viruses from individuals with different clinical outcomes, such as LTNP-ECs, vLTNPs, VNPs, Progressors and RPs to investigate the role of the viral Env protein in HIV-1 pathogenesis. (a) The researchers cloned full-length viral envs in expression plasmids from the viruses of these individuals. The viral clones were completely sequenced at the nucleotide level and submitted to phylogenetic analysis. These viral envs/Envs were analyzed by multiple phenotypic characterizations to see the principal properties of their viruses as presented in the following panels; (b) Env expression: HEK-293T cells were co-transfected with a ptat Δenv HIV-1 expression plasmid together with reference or primary full-length viral env HIV-1 expression plasmid. By using the specific anti-Env antibody, cell-surface Env expression was analyzed by flow cytometry; (c) Env-mediated viral transfer: HEK-293T cells producing HIV-1 virions bearing reference or primary Envs were co-cultured with primary CD4+ T cells. Flow cytometry was used together with specific anti-p24 antibody to measure HIV-1 transfer to CD4+ T cells; (d) Env-mediated fusion activity: HEK-293T cells transfected with the env defective pSG3-HIV-1 backbone and primary envs plasmids (i.e., producing HIV-1 virions) or cells over-expressing the viral Env together with Tat viral protein (pTat construct) were co-cultured with target TZM-bl cells. Then, Env fusion capacity was measured by the magnitude of Tat-induced Luciferase activity in fused cells; (e) Env-mediated viral infection: TZM-bl cells were infected with serial dilutions of HIV-1 virions isolated from HEK-293T cells cotransfected with Δenv pSG3-HIV-1 and with primary or reference HIV-1 Envs. Infectivity capacity was determined in TZM-bl cells by measuring the luciferase activity in HIV-1 infected TZM-bl cells or in CD4+ T CEM.NKR-CCR5 cells by quantifying luciferase activity associated with the enter infectious Δenv pNL4-3.Luc.R-E- pseudovirus carrying primary Env.
Based on these experimental strategies, the researchers reported that Envs from viruses of a cluster of LTNP-EC individuals showed a limited ability to induce both cortical F-actin reorganization and capping, and a low signal stabilizing acetylated MTs in the α-tubulin subunit [100] (Figure 3). These HIV-1 Envs were well expressed at the cell-surface of virus producing cells (Figure 2b). These data correlated with the fact that these Envs were not able to bind to CD4 with high affinity [70][71][72][100][102][104][119][121] (Figure 2c–e and Figure 3). The inability of these ECs’ HIV-1 Envs to bind to CD4 and trigger cell signals to reorganize and modify the cytoskeleton, to generate a pseudopod where cytoskeleton and cell-surface receptors for HIV-1 infection concentrate [100][102][104] (Figure 3), accounts for the defect of the HIV-1 Envs for the promotion of pore fusion formation and transfer of viral material to primary non-infected CD4+ T cells [100] (Figure 2c,d and Figure 3). In addition, a significant correlation was observed between the HIV-1 transfer values, mediated by Env/CD4 binding capacity and fusogenicity, thus linking the fusion defect to a low CD4 affinity (Figure 2c,d). Before characterizing these mechanisms underlying inefficient HIV-1 Envs, the researchers reported non-functional viral Envs in a previous study with non-progressor individuals [26][73][83]. Taken together, these data further confirm the deficient Env fusion capacity observed in the cluster LTNP envelopes, correlating with the inefficiency to infect target cells and replicate at high levels [26][100] (Figure 2e and Figure 3).
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Figure 3. HIV-1 Env-mediated productive cell signals and cell damage: (a) functional HIV-1 Envs of viral isolates from progressors (progressors and RPs) and viremic (VNP) patients efficiently binds to CD4 for the promotion of the F-actin and MTs reorganizations and post-translational modifications. This signal drives pseudopod formation in CD4+ T cells where CD4 and chemokine co-receptors for HIV-1 infection reorganize, aggregate and interact (step 1) [70][72][100][102][104][105][119][121]. These events are required for efficient pore fusion formation, viral transfer, virus entry and infection. On the contrary, non-functional HIV-1 Envs of viral isolates from non-progressors’ patients (LTNP-ECs, LTNP and vLTNP)) are not able to bind to CD4 with high affinity, and thereby are unable to reorganize the cytoskeleton and favour all the events for productive viral transfer and infection (step 2) [70][72][100]; (b) functional HIV-1 Envs of viral isolates from viremic and progressors (VNP and RPs) patients efficiently bind to CD4 to trigger late autophagy with subsequent cell death of non-infected CD4+ T cells (bystander cells) by contact [72].

3. Fully Functional HIV-1 Envs Are Linked to Viremia and Progressor Clinical Phenotypes

For the investigation into the role of viral Env in the control of HIV-1 infection and pathogenesis, the researchers also analyzed viral envs/Envs from other sets of viruses from non-clustered LTNP-EC individuals, followed for more than ten years, in comparison with viruses from patients infected at the same period of time but with progressor phenotypes [70]. In contrast to the Envs from the LTNP EC subjects, the viruses from the progressor individuals (viremic and progressors) showed the opposite properties, with a good affinity for CD4, cell fusion and viral transfer [70][72][100][106]. Therefore, functional HIV-1 Envs are associated with infectious virus and cytopathic activity [71][72], which characterize viremic and progressor/RPs clinical outcomes [70][72][100][106] (Figure 3 and Figure 4). Functional HIV-1 Envs favor the accumulation of mutations that could result in function gains of the Envs and the evasion from immune responses (Figure 3 and Figure 4). During viral transmission to a new host, a selection for viral variants with shorter variable regions and a reduced degree of PNGs occurs in viruses from the HIV-1 subtype B [125]. An increase in viral infectivity and replication capacity has been associated with genetic variability in the env gene [126][127][128][129][130][131]. This viral replication could favor the gain of function of the HIV-1 env by increasing viral fitness and could result in the escape from the immune response and ART [132][133][134][135][136][137][138][139][140]. In the studies, the researchers detected the loss of the N362 PNGs (HXB2 isolate; group M, subtype B (HIV-1 M:B_HXB2R:NCBI:txid11706)), which is frequently observed in the Envs of non-progressor phenotypes (EC and viremic patients) and in long-lasting progressors, but not in HIV-1 Envs from more recent progressors. This change could be related to a gain of functionality observed in these Envs [70]. However, in a study of some Australian viruses presenting the N362 glycosylation site, the viruses showed efficient fusion and transfer capacity [141]. These data reflect the significant effect that point mutations could have in the viral characteristics and HIV pathogenesis [70][100][142][143]. These results indicate that deficient viral Envs are associated with non-progressor, controller individuals and that fully functional HIV-1 Envs are mainly linked to viremic and progressor clinical phenotypes.
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Figure 4. HIV-1 Env function correlates with clinical outcome, immune system activation, exhaustion and cell damage: (a) The researchers' works indicate that HIV-1 Envs of viruses from viremic and progressors patients (i.e., Progressors, RPs and VNPs) are associated with efficient viral infection (step 1, in Progressors) and replication (step 3, in Progressors), favouring viral diversity (step 2, in Progressors) and Env gain of functionality (step 1). This gain is linked with an increasing length of the variable loops (VLs) of the gp120 subunit of the Env viral complex and of N-linked glycosylation sites (PNGs) over the course of the epidemic. These functional Envs trigger cell signals activating target CD4+ T cells. Long-lasting activation leads to immune exhaustion. Progressors HIV-1 patients must follow ART, in order to avoid the development of AIDS; (b) On the contrary, non-functional HIV-1 Envs are associated with viruses of non-progressors HIV-1 individuals (i.e., LTNPs, LTNP-ECs and viremic LTNPs (vLTNPs)) presenting deficiencies in infection (step 1, in non-progressors), viral diversity (step 2, in non-progressors) and replication (step 3, in non-progressors). The HIV-1 envs’ sequences of LTNP-ECs, after thirty years of natural control of viral replication and viral pathogenesis, are close to the sequence of the T/F virus. This poor Env functionality could help the immune system to control the infection, preserving its functions. There are LTNP individuals and particularly LTNP-ECs or exceptional ECs that control HIV-1 infection for up to thirty years without any ART [44]. In this last study as well as in other investigating cases of HIV-1 functional cure, although there was not a direct analysis of Env functionality, all individuals showed undetectable VLs, and defects in viral replication and in the viral genome [44][68][144][145].

4. Role of the Viral Env Complex in Signal Transmission in Other Cellular Process and Cell Death

In addition to these direct viral effects on viral replication, the Env complex is also associated with other important cellular processes like fusion pore formation and autophagy/cell death dysregulation. These processes are summarized in Figure 3. In the characterization of these HIV-1 Envs properties, the researchers analyzed HIV-1 Envs from viremic non-progressors (VNPs), progressors and rapid progressors (RPs) patients [44][70][72][73][100][106]. The phenotypic characterization of the Envs from HIV-1 progressors (Figure 3 and Figure 4) indicated higher replication capacity for these HIV-1 viruses when compared with HIV-1 Envs of viruses from the LTNP-EC cluster [100]. HIV-1 Envs from progressors patients are associated with functional Env showing efficient CD4 binding and signaling that promote cytoskeleton reorganization and the formation of the pseudopod-hot region. This process allows an efficient HIV-1 infection (Figure 3a) which leads to higher fusogenic, viral transfer and infection capacities than viruses from LTNP-ECs [70][100]. It is noteworthy that the researchers reported that the HIV-1 gp41-Env subunit promotes bystander cell-death by autophagy and apoptosis [91][92][93][94][95][96]. The researchers' works indicate that functional HIV-1 Envs from VNPs and RPs promote bystander cell death in uninfected CD4+ T cells by triggering late autophagy [71][72] (Figure 3b). In line with this Env functionality, the researchers found significant env gene diversity in sequences isolated from VNPs compared with RPs, correlating with the efficient ability of these VNP HIV-1 Envs to infect and favor virus replication [72]. A similar observation has been reported indicating that viral population diversity remains higher in VNPs compared to standard progressors or RPs [146]. Persistent HIV-1 replication in the presence of supposedly efficient immune responses in VNPs is expected to lead to the accumulation of mutations to compensate viral fitness cost, which could result in a continuous Env escape from neutralizing Abs [147][148]. Furthermore, in the late AIDS phase of chronic infection in RPs, uncontrolled HIV-1 replication occurs together with the selection of the fittest variants [149]. Therefore, functional HIV-1 Envs are directly associated with infectious viruses of viremic and progressors patients in which HIV-1 infection evolves [70][71][72][106] (Figure 1, Figure 3 and Figure 4). This efficient viral function of the HIV-1 Env, in a CD4 dependent manner, allows the virus to overcome cell barriers that limit HIV-1 Env-mediated pore fusion formation, viral entry to the cell, infection and replication (Figure 3a). A key restriction factor for HIV-1 infection that the researchers characterized is the cytoplasmic enzyme HDAC6 (histone deacetylase 6) [70][71][72][105][106][121][150], and more recently the transactive response of the DNA-binding protein (TARDBP or TDP-43) together with HDAC6 (i.e., the TDP-43/HDAC6 axis) [106]. An increase in the expression of functional TDP-43 concomitantly enhances the levels of mRNA and protein of HDAC6, leading to a diminution of the activity of functional HIV-1 Envs from viruses of VNP and RP individuals, reaching the levels of the inefficient Env from LTNP-EC individuals [106]. Silencing of the endogenous TDP-43 strongly reduces the levels of mRNA and of the HDAC6 enzyme [106], stabilizing acetylated MTs that favor the infection activity of primary HIV-1 Envs of VNP, progressors and even of non-functional Envs from LTNP-EC individuals [106]. This last observation suggests that defective viral features observed in a virus of LTNP-ECs [70][71][100][151] are possibly also modulated by the TDP-43/HDAC6 axis [106]. The TDP-43/HDAC6 axis therefore regulates cell permissivity to HIV-1 infection. This point may have negative consequences in HIV-1 LTNP-EC individuals, particularly if a negative regulation of TDP-43 occurs with a concomitant decrease in HDAC6 that would render cells more permissive against inefficient LTNP-EC Envs. Consistently, it has been reported that the ability of the viral Env to trigger signals that overcome the HDAC6 barrier is directly related to its fusion and infection activities [70][72][100][105][121]. The TDP-43/HDAC6 axis could be another factor that is worth exploring in EC individuals that lose the natural control of the infection [70][72][100][105][121][152].

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