Advance in treatment strategy and immune reconstruction against HIV-1 infection

HIV-1 can be considered an infection of the immune system, resulting in progressive and ultimately profound immune suppression. The availability of highly active antiretroviral therapy (HAART) has resulted in dramatic changes in the disease course in persons fortunate enough to have access to these medications, but long-term therapy is limited by the development of resistance as well as toxicities of the potent medication regimens. Emerging data indicate that individuals who have non-progressive clinical course control HIV-1 immunologically. This has bolstered hope that the immune response might be effectively augmented in persons with HIV infection. Recent data indicating that immediate treatment of acute infection leads to augmentation of antiviral immune responses have provided evidence that the immune system might be enhanced in certain situations. Therefore, investigation in the reconstitution of anti-HIV immune response in patients under HAART should provide encouragement for continuing to explore methods to obtain meaningful and durable immune enhancement as an adjunct to HAART in HIV-1 infection.     

ADCC-mediating non-neutralizing antibodies can exert immune pressure in early HIV-1 infection

Despite antibody-dependent cellular cytotoxicity (ADCC) responses being implicated in protection from HIV-1 infection, there is limited evidence that they control virus replication. The high mutability of HIV-1 enables the virus to rapidly adapt, and thus evidence of viral escape is a very sensitive approach to demonstrate the importance of this response. To enable us to deconvolute ADCC escape from neutralizing antibody (nAb) escape, we identified individuals soon after infection with detectable ADCC responses, but no nAb responses. We evaluated the kinetics of ADCC and nAb responses, and viral escape, in five recently HIV-1-infected individuals. In one individual we detected viruses that escaped from ADCC responses but were sensitive to nAbs. In the remaining four participants, we did not find evidence of viral evolution exclusively associated with ADCC-mediating non-neutralizing Abs (nnAbs). However, in all individuals escape from nAbs was rapid, occurred at very low titers, and in three of five cases we found evidence of viral escape before detectable nAb responses. These data show that ADCC-mediating nnAbs can drive immune escape in early infection, but that nAbs were far more effective. This suggests that if ADCC responses have a protective role, their impact is limited after systemic virus dissemination.     

Functional adaptation of Nef to the immune milieu of HIV-1 infection in vivo

Nef-mediated down-regulation of MHC class I (MHC-I) molecules on HIV-1-infected cells has been proposed to enhance viral persistence through evasion of host CTLs. This conclusion is based largely on demonstrations that Nef from laboratory HIV-1 strains reduces the susceptibility of infected cells to CTL killing in vitro. However, the function and role of Nef-mediated MHC-I down-regulation in vivo have not been well described. To approach this issue, nef quasispecies from chronically HIV-1-infected individuals were cloned into recombinant reporter viruses and tested for their ability to down-regulate MHC-I molecules from the surface of infected cells. The level of function varied widely between individuals, and although comparison to the immunologic parameters of blood CD4(+) T lymphocyte count and breadth of the HIV-1-specific CTL response showed positive correlations, no significant correlation was found in comparison to plasma viremia. The ability of in vivo-derived Nef to down-regulate MHC-I predicted the resistance of HIV-1 to suppression by CTL. Taken together, these data demonstrate the functionality of Nef to down-regulate MHC-I in vivo during stable chronic infection, and suggest that this function is maintained by the need of HIV-1 to cope with the antiviral CTL response.     

Potential role of immune modulation in the effective long-term control of HIV-1 infection

Recent advances in HIV-1 pathogenesis, and in defining virological and immunological responses to highly active antiretroviral therapy (HAART), along with the identification of the numerous drawbacks of HAART, have clearly demonstrated that the eradication of the virus is not a feasible therapeutic goal, and that there is an urgent need to develop other approaches to fight HIV-1 infection. Novel therapeutic approaches of immune modulation have recently been evaluated in pilot clinical trials. First, treating primary HIV-1 infection with cyclosporin A (CsA) coupled with HAART to target massive immune activation extends the benefits achieved with HAART during primary HIV-1 infection and might contribute to the establishment of a more favourable immunological set-point affecting the ultimate pattern and rate of disease progression. Second, treating chronic HIV-1 infection in patients with long-term suppression of virus replication induced by HAART, with the addition of mycophenolate mofetil (MMF) reduces the pool of activated CD4+ T lymphocytes able to support productive HIV-1 infection, and might have an indirect impact on the pool of resting, latently infected CD4+ T cells, contributing to its depletion in vivo. The important question is clearly whether these results will have an impact on the clinical management of patients with HIV-1 infection, determining the precise therapeutic function of drugs like CsA and MMF, thus investigating the effects of these drugs on residual viral replication and the decay of the latent reservoir, on long-term immunological benefit, and, ultimately, on clinical benefit.     

Mathematical modeling of viral kinetics under immune control during primary HIV-1 infection

Primary human immunodeficiency virus (HIV) infection is characterized by an initial exponential increase of viral load in peripheral blood reaching a peak, followed by a rapid decline to the viral setpoint. Although the target-cell-limited model can account for part of the viral kinetics observed early in infection [Phillips, 1996. Reduction of HIV concentration during acute infection: independence from a specific immune response. Science 271 (5248), 497-499], it frequently predicts highly oscillatory kinetics after peak viremia, which is not typically observed in clinical data. Furthermore, the target-cell-limited model is unable to predict long-term viral kinetics, unless a delayed immune effect is assumed [Stafford et al., 2000. Modeling plasma virus concentration during primary HIV infection. J. Theor. Biol. 203 (3), 285-301]. We show here that extending the target-cell-limited model, by implementing a saturation term for HIV-infected cell loss dependent upon infected cell levels, is able to reproduce the diverse observed viral kinetic patterns without the assumption of a delayed immune response. Our results suggest that the immune response may have significant effect on the control of the virus during primary infection and may support experimental observations that an anti-HIV immune response is already functional during peak viremia.     

NKT cells in HIV-1 infection

Natural killer T （NKT） cells are a unique T cell population that have important immunoregulatory functions and have been shown to be involved in host immunity against a range of microorganisms. It also emerges that they might play a role in HIV-1 infection, and therefore be selectively depleted during the early stages of infection. Recent studies are reviewed regarding the dynamics of NKT depletion during HIV-1 infection and their recovery under highly active antiretroviral treatment （HAART）. Possible mechanisms for these changes are proposed based on the recent developments in HIV pathogenesis. Further discussions are focused on HIV＇s disruption of NKT activation by downregulating CDld expression on antigen presentation cells （APC）. HIV-1 protein Nefis found to play the major role by interrupting the intracellular trafficking of nascent and recycling CDld molecules.     

HIV-1感染的共受体

早在1984年就已发现人免疫缺陷病毒一I型（HIV－l）感染细胞是通过与细胞表面受体CDe结合而进行的,但两年后又发现表达CDe的非人类细胞不能被IlfV－l感染,因此有人认为仅有CDe作为H］V－l的受体是不够的,还必须有人类细胞特异表达的某种辅助因子。最近,一些与CDe偶联的HIV则共受体已被陆续鉴定,它们均为趋化因子（chemokjnes受体家族的成员,也正是H］V－l感染所必需的辅助因子。互作为HIV—且共受体的趋化因子受体CXCR4是第一个被发现具有I］：IV－l共受体作用的蛋白质I’］,最初称为融合素（fusin）、LESTR等。最近…     

HIV-1-specific cellular immune responses among HIV-1-resistant sex workers

The goal of the present study was to determine whether there were HIV-1 specific cellular immune responses among a subgroup of women within a cohort of Nairobi prostitutes (n = 1800) who, despite their intense sexual exposure to HIV-1, are epidemiologically resistant to HIV-1 infection. Of the 80 women defined to be resistant, 24 were recruited for immunological evaluation. The HIV-1-specific T-helper responses were determined by IL-2 production following stimulation with HIV-1 envelope peptides and soluble gp120. Cytotoxic T lymphocyte responses were determined by lysis of autologous EBV-transformed B cell lines infected with control vaccinia virus or recombinant vaccinia viruses containing the HIV-1 structural genes env, gag and pol. Resistant women had significantly increased HIV-1 specific T-helper responses, as determined by in vitro IL-2 production to HIV-1 envelope peptides and soluble glycoprotein 120, compared with low-risk seronegative and HIV-1-infected controls (P < or = 0.01, Student's t-test). Seven of the 17 (41%) resistant women showed IL-2 stimulation indices > or = 2.0. HIV-1-specific CTL responses were detected among 15/22 (68.2%) resistant women compared with 0/12 low-risk controls (Chi-squared test, P < 0.001). In the two resistant individuals tested, the CTL activity was mediated by CD8+ effectors. Many HIV-1-resistant women show evidence of HIV-1-specific T-helper and cytotoxic responses. These data support the suggestion that HIV-1-specific T-cell responses contribute to protection against HIV-1 infection.     

HIV-1 GP120-mediated immune suppression and lymphocyte destruction in the absence of viral infection

The magnitude of immunologic defects observed in HIV-1-infected individuals before the development of overt AIDS is disproportionately high in comparison to the levels of infectious virus in these patients--suggesting that factors other than direct virus-induced cytopathology may be involved. With this in mind, we investigated the immunologic consequences of the interaction between purified HIV-1 gp120 and the CD4 molecules expressed by uncommitted as well as Ag-specific lymphocytes. HIV-1 gp120 exhibited a dose-dependent immunosuppressive effect on: 1) Ag-driven proliferation of cloned CD4+ lymphocytes, 2) OKT3-driven proliferation of cloned CD4+ lymphocytes, and 3) cytolytic activity of CD4+, EBV-specific CTL. Thus, HIV-1 gp120 can, in a manner similar to OKT4A antibodies, suppress T cell activation and the expression of cytolytic activities through its interaction with CD4. Additionally, activated CD4+ lymphoblasts can be rendered susceptible to immune cytolysis by virtue of their binding of purified gp120. This "targeting" of activated lymphoblasts can occur with levels of gp120 far below that which is needed to saturate all OKT4A-defined CD4 epitopes. Adsorbed gp120 could be demonstrated on the surface of these cells for up to 12 h, a sufficient time for interaction with host cytolytic elements. The data from these in vitro modeling experiments highlight one of many potential mechanisms of HIV-1 induced immunosuppression and lymphocyte destruction that can occur in the absence of infectious virus and that is based on the unique interaction between HIV-1 gp120 and its cellular receptor, CD4.     

Plasma membrane signaling in HIV-1 infection

Plasma membrane is a multifunctional structure that acts as the initial barrier against infection by intracellular pathogens. The productive HIV-1 infection depends upon the initial interaction of virus and host plasma membrane. Immune cells such as CD4 + T cells and macrophages contain essential cell surface receptors and molecules such as CD4, CXCR4, CCR5 and lipid raft components that facilitate HIV-1 entry. From plasma membrane HIV-1 activates signaling pathways that prepare the grounds for viral replication. Through viral proteins HIV-1 hijacks host plasma membrane receptors such as Fas, TNFRs and DR4/DR5, which results in immune evasion and apoptosis both in infected and uninfected bystander cells. These events are hallmark in HIV-1 pathogenesis that leads towards AIDS. The interplay between HIV-1 and plasma membrane signaling has much to offer in terms of viral fitness and pathogenicity, and a better understanding of this interplay may lead to development of new therapeutic approaches. This article is part of a Special Issue entitled: Viral Membrane Proteins — Channels for Cellular Networking.     

Analysis of the systemic immune response in HIV-1-infected patients suffering from opportunistic Candida infection

Infection by HIV-1 is a major risk factor predisposing for fungal infection. However, few studies have addressed the immunological status of HIV-1 patients suffering fungal infections. This study examines the status of polymorphonuclear phagocytes (PMN) and T cells in HIV-1-infected patients suffering from mucosal Candida infections. These patients had a more immature population of blood PMN, as detected by lower CD18 expression, than HIV asymptomatics or healthy controls. They also had a selective defect in T cell activation in response to phytohemagglutinin (PHA), but not to stimulation through the T cell receptor by anti-CD3 crosslinking, when compared to HIV-1 asymptomatic patients. This was shown by a decrease in cellular proliferation and cell surface expression of CD69, CD25 and CD71 activation antigens. There was also a severe impairment of IL-2 production upon activation by PHA. IL-10, and TNF secretion was also reduced, whereas IFN-gamma and IL-5 production was not affected. No correlation with viral load, CD4 or CD8 T cell number or clinical stage was found. In conclusion, our results indicate that Candida-infected HIV patients have a selective defect, independent of viral load, CD4 or clinical status, involving some aspects of T cell activation, IL-2 production being severely impaired.     

NK cell function in HIV-1 infection

NK cells are critical effector cells of the innate immune response to malignancy and infection. These cells have a wide array of direct antiviral activities and have been critically implicated in the regulation and induction of an effective adaptive immune response. Although the pivotal role of this cell subset in the context of a number of viral infections is well established, the role of NK cells in HIV-1 infection is less well understood. Recent data has demonstrated the association between an NK cell receptor, KIR3DS1, and it's ligand, HLA-Bw4 with an isoleucine at position 80, and slower disease progression. This data suggests that NK cells may play an essential role in the control of HIV-1 disease, and has provided the impetus to begin to better understand the role of this cell subset in the context of HIV-1 infection, replication, and pathogenesis. Here we present a review of the literature pertaining to both the effect of HIV-1 infection on NK cell activity and the potential role that this subset of cells may play in controlling HIV-1 disease.     

Dynamic antibody specificities and virion concentrations in circulating immune complexes in acute to chronic HIV-1 infection

Understanding the interactions between human immunodeficiency virus type 1 (HIV-1) virions and antibodies (Ab) produced during acute HIV-1 infection (AHI) is critical for defining antibody antiviral capabilities. Antibodies that bind virions may prevent transmission by neutralization of virus or mechanically prevent HIV-1 migration through mucosal layers. In this study, we quantified circulating HIV-1 virion-immune complexes (ICs), present in approximately 90% of AHI subjects, and compared the levels and antibody specificity to those in chronic infection. Circulating HIV-1 virions coated with IgG (immune complexes) were in significantly lower levels relative to the viral load in acute infection than in chronic HIV-1 infection. The specificities of the antibodies in the immune complexes differed between acute and chronic infection (anti-gp41 Ab in acute infection and anti-gp120 in chronic infection), potentially suggesting different roles in immunopathogenesis for complexes arising at different stages of infection. We also determined the ability of circulating IgG from AHI to bind infectious versus noninfectious virions. Similar to a nonneutralizing anti-gp41 monoclonal antibody (MAb), purified plasma IgG from acute HIV-1 subjects bound both infectious and noninfectious virions. This was in contrast to the neutralizing antibody 2G12 MAb that bound predominantly infectious virions. Moreover, the initial antibody response captured acute HIV-1 virions without selection for different HIV-1 envelope sequences. In total, this study demonstrates that the composition of immune complexes are dynamic over the course of HIV-1 infection and are comprised initially of antibodies that nonselectively opsonize both infectious and noninfectious virions, likely contributing to the lack of efficacy of the antibody response during acute infection.