Current HIV Research - Volume 2, Issue 1, 2004

Around the world, approximately 5 million people became infected with HIV in 2001, an estimated 70% via sexual transmission. Numerous studies have demonstrated that it is difficult to achieve total protection from vaginally or rectally acquired HIV / SIV when using parenteral immunization. Mucosal immunization was seen as the best approach to achieve sustainable immune responses at mucosal sites of viral entry. This was further emphasized when several studies implicated rectal and vaginal mucosa as latent reservoirs for the HIV virus and virus-specific CD8+ T cell immune responses in gastrointestinal mucosa were shown to be less efficient than in systemic tissues. Mucosal vaccines utilizing various routes of immunization including intranasal, intrarectal, intravaginal and oral immunization have been tested for their potency to induce virus-specific immune responses systemically but especially at mucosal sites of viral entry. The unsatisfactory results in initiating simultaneously sufficient immune responses at mucosal and systemic sites are being overcomed by use of appropriate and novel adjuvants such as Cholera toxin, Escherichia coli heat-labile toxin, immunostimulatory CpG motifs, coinjection of cytokines and others. Various routes of immunization are now being compared and combinations of mucosal immunization and parenteral boost and vice versa have also been tested. Generations of new vaccines, such as DNA-based vaccines, multipeptide, lipopeptide and alphavirus replicon particles-based vaccines have been created and studied for their efficiency.

HIV establishes a chronic and latent infection that is not eliminated by the host immune defences. The virus induces extensive damage to the immune system, through virus-related and indirect pathogenic mechanisms. Both the cellular and the humoral arms of the immune system are unable to control the infection, which ultimately results in severe exhaustion of several lymphocyte functions and increased susceptibility to secondary and opportunistic infections. A striking pathological feature induced by the persistent viral replication is the aberrant activation of cells of the immune system. Among these cells, B lymphocytes are severely damaged and show signs of phenotypic and functional alterations. In parallel to the polyclonal B cell activation and hypergammaglobulinemia, B cells from patients show impaired reactivity to immunisation and in vitro activation signals. In addition, B lymphocytes from HIV-infected subjects are primed for apoptosis. The role of protective humoral immunity in the control and clinical progression of HIV infection is still much debated and controversial. The aim of the present review is to discuss the mechanisms involved in the loss of B cell functions during HIV infection. In particular, we discuss the role that T and B cell immune activation plays for B cell polyclonal activation and loss of memory B lymphocytes. The current knowledge on B cell damage is also discussed in the context of anti-HIV therapeutic treatment.

CD8+ T-cells are a critical component of the cellular immune response and they play an important role in the control of viral infection. During HIV infection, CD8+ T-cells are able to recognize infected cells through an MHC-I dependent process and are able to lyse cells harboring viral infection by the secretion of perforin and granzymes. These cytotoxic T-lymphocytes (CTL) can also eliminate virally infected cells through the engagement of death-inducing ligands expressed by CD8+ T-cells with death receptors on the surface of the infected cell. In addition, CD8+ CTL secrete soluble factors such as β-chemokines and the CD8+ antiviral factor (CAF) that suppress viral binding and transcription, respectively. In order for HIV to survive the pressures placed upon it by the immune system, the virus has adopted numerous strategies to evade the CD8+ T-cell response. The high mutation rate of HIV has allowed the virus to escape CD8+ T-cell recognition in addition to its ability to down-regulate surface MHC-I expression from infected cells. Also, by altering the pattern of cytokine production and engagement of cellular receptors, HIV disrupts proper CD8+ T-cell signaling. The resultant improper T-cell receptor (TcR) stimulation creates an anergic state in these cells. By affecting the function of CD4+ T-cells and antigen presenting cells that are required for proper CD8+ T-cell maturation, HIV is able to decrease the circulating pool of effector and memory CD8+ T-cells that are able to combat viral infection. The end result is the aberration of CD8+ T-cell function.

In addition to the CD4 molecule that binds to the human immunodeficiency virus type-1 (HIV-1) envelope glycoprotein gp120, productive HIV-1 infection requires interaction with cellular receptors for α- or β- chemokines (CXCR4 and CCR5 respectively). Isolates of HIV-1 exhibit different tropism depending on the chemokine receptor type that they use to infect their cellular targets. HIV-1 strains that use preferentially CCR5 are known as R5 strains. They are more frequently found in asymptomatic individuals during the initial stages of the disease and are involved in the transmision of infection from mother to child. HIV-1 species using CXCR4 (X4 strains) are observed mainly in patients with advanced disease. While X4 isolates are associated with syncitium formation, in general R5 strains are not. Interaction of X4 and R5 with their specific receptors is necessary to establish productive HIV-1 infection and trigger a series of intracellular signals. Modulation of CXCR4 and CCR5 expression after HIV-1 infection is one of the results of such interaction and may have important consequences on the course of the infection. Down regulation of CCR5 and CXCR4 after HIV-1 infection could be the result of indirect events linked to HIV-1 infection, such as the induction of α- or β-chemokines competing with the virions for receptor binding. They could also reflect direct effects of HIV-1 on chemokine-receptor turnover. In this review, the mechanisms of modulation of CXCR4 and CCR5 expression after HIV-1 infection will be discussed.

Human immunodeficiency virus has evolved several redundant mechanisms to remove its receptor, the CD4 molecule, from the cell surface. Indeed, HIV-1 encodes three proteins, Nef, Vpu and Env, that have a profound effect on CD4 trafficking and catabolism. Given this functional convergence, it is believed that cell surface CD4 regulation constitutes an important determinant of viral replication and pathogenesis in vivo. This review highlights recent progress made in our understanding of the molecular mechanisms underlying the down-regulation of the CD4 receptor by HIV-1 and describes our current comprehension of the role of CD4 down-regulation during HIV-1 infection.

Persons with advanced human immunodeficiency virus type one (HIV-1) infection seek medical advice for a wide range of neurological disorders including, but not limited to, peripheral neuropathy, toxoplasmosis, cryptococcal meningitis, cytomegalovirus retinitis progressive multifocal leukoencephalopathy, lymphoma and dementia. The diagnosis of HIV-1-associated dementia (HAD) induced as a direct consequence of HIV infection of the brain comes commonly by exclusion. Diagnostic decisions can often be clouded by concomitant depression, motor impairments, and lethargy that follow debilitating immune suppression and weight loss. Indeed, cognitive, motor and behavior abnormalities underlie a variety of neurological dysfunctions associated with advanced HIV-1 infection. Thus, even combinations of clinical, laboratory and neuroimaging tests [for example, magnetic resonance imaging (MRI), computed tomography (CT), single photon emission computed tomography (SPECT) and positron emission tomography (PET)] often fail to provide conclusive diagnostic information. Nonetheless, the recent development of quantitative MR spectroscopic imaging has improved diagnostic possibilities for HAD. We are pleased to discuss these developments as well as taking a forward look into what will soon be made available to improve neuroimaging diagnostic precision. New MR and SPECT testing are being developed in our laboratories and elsewhere both for animal model systems and in humans with HIV-1 disease. Such tests can facilitate dynamic measures of HIV-1 neuropathogenesis providing information for disease events that even 2 years ago were unattainable.

In the following three sections we will briefly review the seminal roles of the HIV-1 nucleocapsid protein NCp7 in the fate of the HIV-1 full length RNA from genomic RNA in a dimeric form to the proviral DNA. Emphasis will be given to the mechanisms of NC-directed assistance to the genomic RNA and reverse transcriptase in the course of proviral DNA synthesis and to DNA integrity at the end of the polymerization process, and to the NC-assisted repair and recombination reactions fueling the viability and variability of the virus.

Correction to “Regulation of TAK / P-TEFb in CD4+T Lymphocytes and Macrophages” by Andrew P. Rice and Christine H. Herrmann published in Current HIV Research, October 2003, Vol. 1, No. 4, pp. 395-404. The correct figure 4 is given below. Earlier it missed some characters. The publishers regret any inconvenience.