The role of viral coreceptors and enhanced macrophage tropism in human immunodeficiency virus type 1 disease progression

Sexual Health ◽  
2004 ◽  
Vol 1 (1) ◽  
pp. 23 ◽  
Author(s):  
Paul R. Gorry ◽  
Jasminka Sterjovski ◽  
Melissa Churchill ◽  
Kristie Witlox ◽  
Lachlan Gray ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Disease Progression ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Molecular Mechanisms ◽  
Coreceptor Usage ◽  
Immunodeficiency Virus ◽  
The Impact ◽  
Hiv 1

Despite numerous studies on the impact of viral diversity, human immunodeficiency virus type 1 (HIV-1)-specific immune responses and host factors on disease progression, we still do not have a firm understanding of the long-term pathogenesis of HIV-1 infection. Rapid depletion of CD4+ T-lymphocytes has been associated with a switch in viral coreceptor usage from CCR5 to CXCR4 in ~40 to 50% of infected individuals. However, the majority of infected individuals who progress to AIDS harbour only CCR5-dependent (R5) viral strains. The progression HIV-1 disease is associated with an enhanced tropism of R5 viral strains for monocyte/macrophage lineage cells (enhanced M-tropism). However, the underlying molecular mechanisms contributing to enhanced M-tropism by R5 HIV-1 strains, and how HIV-1 variants with enhanced M-tropism cause CD4+ T-cell depletion in vivo are unknown. This review examines the relationship between viral coreceptor usage, M-tropism, and pathogenicity of HIV-1. We highlight evidence supporting the hypothesis that enhanced M-tropism of R5 HIV-1 results from adaptive viral evolution, resulting in HIV-1 variants that have increased ability to utilise relatively low levels of CCR5 expressed on macrophages, by way of increased CCR5 affinity. The evidence also suggests that these late-emerging, R5 viral strains have reduced sensitivity to entry inhibitors, and increased ability to cause CD4+ T-lymphocyte loss. These variants are likely to impact HIV-1 disease progression, especially in patients who persistently harbour only R5 viral strains.

scholarly journals Interaction between the Human Immunodeficiency Virus Type 1 Gag Matrix Domain and Phosphatidylinositol-(4,5)-Bisphosphate Is Essential for Efficient Gag Membrane Binding

2007 ◽  
Vol 82 (5) ◽  
pp. 2405-2417 ◽  
Author(s):  
Vineela Chukkapalli ◽  
Ian B. Hogue ◽  
Vitaly Boyko ◽  
Wei-Shau Hu ◽  
Akira Ono
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Molecular Mechanisms ◽  
Membrane Binding ◽  
Particle Assembly ◽  
Immunodeficiency Virus ◽  
The Impact ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) particle assembly mediated by the viral structural protein Gag occurs predominantly on the plasma membrane (PM). Although it is known that the matrix (MA) domain of Gag plays a major role in PM localization, molecular mechanisms that determine the location of assembly remain to be elucidated. We observed previously that overexpression of polyphosphoinositide 5-phosphatase IV (5ptaseIV) that depletes PM phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2] impairs virus particle production and redirects processed Gag to intracellular compartments. In this study, we examined the impact of PI(4,5)P2 depletion on the subcellular localization of the entire Gag population using Gag-fluorescent protein chimeras. Upon 5ptaseIV overexpression, in addition to perinuclear localization, Gag also showed a hazy cytosolic signal, suggesting that PI(4,5)P2 depletion impairs Gag membrane binding. Indeed, Gag was less membrane bound in PI(4,5)P2-depleted cells, as assessed by biochemical analysis. These observations are consistent with the hypothesis that Gag interacts with PI(4,5)P2. To examine a putative Gag interaction with PI(4,5)P2, we developed an in vitro binding assay using full-length myristoylated Gag and liposome-associated PI(4,5)P2. Using this assay, we observed that PI(4,5)P2 significantly enhances liposome binding of wild-type Gag. In contrast, a Gag derivative lacking MA did not require PI(4,5)P2 for efficient liposome binding. To analyze the involvement of MA in PI(4,5)P2 binding further, we examined MA basic amino acid substitution mutants. These mutants, previously shown to localize in perinuclear compartments, bound PI(4,5)P2-containing liposomes weakly. Altogether, these results indicate that HIV-1 Gag binds PI(4,5)P2 on the membrane and that the MA basic domain mediates this interaction.

scholarly journals The intra-host evolutionary and population dynamics of human immunodeficiency virus type 1: a phylogenetic perspective

2013 ◽  
Vol 5 (1S) ◽  
pp. 3 ◽  
Author(s):  
Marco Salemi
Keyword(s):  
Human Immunodeficiency Virus ◽  
Population Dynamics ◽  
Disease Progression ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Immunodeficiency Virus ◽  
The Impact ◽  
Hiv 1 ◽  
Over Time

The intra-host evolutionary and population dynamics of the human immunodeficiency virus type 1 (HIV-1), the cause of the acquired immunodeficiency syndrome, have been the focus of one of the most extensive study efforts in the field of molecular evolution over the past three decades. As HIV-1 is among the fastest mutating organisms known, viral sequence data sampled over time from infected patients can provide, through phylogenetic analysis, significant insights about the tempo and mode of evolutionary processes shaped by complex interaction with the host milieu. Five main aspects are discussed: the patterns of HIV-1 intra-host diversity and divergence over time in relation to different phases of disease progression; the impact of selection on the temporal structure of HIV-1 intra-host genealogies inferred from longitudinally sampled viral sequences; HIV-1 intra-host sub-population structure; the potential relationship between viral evolutionary rate and disease progression and the central evolutionary role played by recombination occurring in super-infected cells.

scholarly journals Human immunodeficiency virus type 1 gp120 envelope characteristics associated with disease progression differ in family members infected with genetically similar viruses

2013 ◽  
Vol 94 (1) ◽  
pp. 20-29 ◽  
Author(s):  
Elly Baan ◽  
Renée M. van der Sluis ◽  
Margreet E. Bakker ◽  
Vincent Bekker ◽  
Dasja Pajkrt ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Disease Progression ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Positive Charge ◽  
Gp120 Envelope ◽  
Immunodeficiency Virus ◽  
Virus Strains ◽  
Hiv 1

The human immunodeficiency virus type 1 (HIV-1) envelope protein provides the primary contact between the virus and host, and is the main target of the adaptive humoral immune response. The length of gp120 variable loops and the number of N-linked glycosylation events are key determinants for virus infectivity and immune escape, while the V3 loop overall positive charge is known to affect co-receptor tropism. We selected two families in which both parents and two children had been infected with HIV-1 for nearly 10 years, but who demonstrated variable parameters of disease progression. We analysed the gp120 envelope sequence and compared individuals that progressed to those that did not in order to decipher evolutionary alterations that are associated with disease progression when individuals are infected with genetically related virus strains. The analysis of the V3-positive charge demonstrated an association between higher V3-positive charges with disease progression. The ratio between the amino acid length and the number of potential N-linked glycosylation sites was also shown to be associated with disease progression with the healthier family members having a lower ratio. In conclusion in individuals initially infected with genetically linked virus strains the V3-positive charges and N-linked glycosylation are associated with HIV-1 disease progression and follow varied evolutionary paths for individuals with varied disease progression.

scholarly journals Breadth of Neutralizing Antibody Response to Human Immunodeficiency Virus Type 1 Is Affected by Factors Early in Infection but Does Not Influence Disease Progression

2009 ◽  
Vol 83 (19) ◽  
pp. 10269-10274 ◽  
Author(s):  
Anne Piantadosi ◽  
Dana Panteleeff ◽  
Catherine A. Blish ◽  
Jared M. Baeten ◽  
Walter Jaoko ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Load ◽  
Disease Progression ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Neutralizing Antibody ◽  
Subtype B ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The determinants of a broad neutralizing antibody (NAb) response and its effect on human immunodeficiency virus type 1 (HIV-1) disease progression are not well defined, partly because most prior studies of a broad NAb response were cross-sectional. We examined correlates of NAb response breadth among 70 HIV-infected, antiretroviral-naïve Kenyan women from a longitudinal seroincident cohort. NAb response breadth was measured 5 years after infection against five subtype A viruses and one subtype B virus. Greater NAb response breadth was associated with a higher viral load set point and greater HIV-1 env diversity early in infection. However, greater NAb response breadth was not associated with a delayed time to a CD4+ T-cell count of <200, antiretroviral therapy, or death. Thus, a broad NAb response results from a high level of antigenic stimulation early in infection, which likely accounts for prior observations that greater NAb response breadth is associated with a higher viral load later in infection.

Elevated Levels of Serum-Soluble CD14 in Human Immunodeficiency Virus Type 1 (HIV-1) Infection: Correlation to Disease Progression and Clinical Events

Blood ◽  
1998 ◽  
Vol 92 (6) ◽  
pp. 2084-2092 ◽  
Author(s):  
Egil Lien ◽  
Pål Aukrust ◽  
Anders Sundan ◽  
Fredrik Müller ◽  
Stig S. Frøland ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Disease Progression ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cell Number ◽  
Clinical Events ◽  
Immunodeficiency Virus ◽  
Hiv 1

Abstract Soluble (s) CD14, a marker for monocyte/macrophage activation and a mediator of bacterial lipopolysaccharide (LPS) action, was elevated in serum from human immunodeficiency virus type 1 (HIV- 1)-infected individuals (n = 92) compared with seronegative controls. The highest levels were found in patients with advanced clinical and immunological disease. Patients with ongoing clinical events had significantly higher sCD14 levels than symptomatic HIV-1-infected individuals without clinical events, with especially elevated levels in patients infected with Mycobacterium avium complex (MAC). On longitudinal testing of patients (n = 26) with less than 100 × 106CD4 lymphocytes/L at baseline, we found that increasing sCD14 serum concentrations per time unit were associated with death, whereas no differences in CD4 cell number decrease were found between survivors and nonsurvivors. In vitro studies showed that HIV-1 glycoprotein 120 and purified protein derivative (PPD) from M avium (MAC-PPD) stimulated normal monocytes to release sCD14. Furthermore, MAC-PPD induced tumor necrosis factor (TNF) release from monocytes through interactions with CD14 and, importantly, the addition of sCD14 enhanced this MAC-PPD stimulatory effect. Our findings suggest that the CD14 molecule may be involved in the immunopathogenesis of HIV-1 infection, and it is conceivable that serial determination of sCD14 may give useful predictive information concerning disease progression and survival in HIV-1-infected patients. © 1998 by The American Society of Hematology.

scholarly journals Evolution of the human immunodeficiency virus type 1 protease: effects on viral replication capacity and protease robustness

2012 ◽  
Vol 93 (12) ◽  
pp. 2625-2634 ◽  
Author(s):  
Elena Capel ◽  
Glòria Martrus ◽  
Mariona Parera ◽  
Bonaventura Clotet ◽  
Miguel Angel Martínez
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Replication Capacity ◽  
Recombinant Viruses ◽  
Subtype B ◽  
Immunodeficiency Virus ◽  
The Impact ◽  
Hiv 1

The rapid spread of human immunodeficiency virus type 1 (HIV-1) in humans has been accompanied by continuous extensive genetic diversification of the virus. The aim of this study was to investigate the impact of HIV-1 diversification on HIV-1 replication capacity (RC) and mutational robustness. Thirty-three HIV-1 protease sequences were amplified from three groups of viruses: two naïve sample groups isolated 15 years apart plus a third group of protease inhibitor-(PI) resistant samples. The amplified proteases were recombined with an HXB2 infectious clone and RC was determined in MT-4 cells. RC was also measured in these three groups after random mutagenesis in vitro using error-prone PCR. No significant RC differences were observed between recombinant viruses from either early or recent naïve isolates (P = 0.5729), even though the proteases from the recent isolates had significantly lower sequence conservation scores compared with a subtype B ancestral sequence (P<0.0001). Randomly mutated recombinant viruses from the three groups exhibited significantly lower RC values than the corresponding wild-type viruses (P<0.0001). There was no significant difference regarding viral infectivity reduction between viruses carrying randomly mutated naïve proteases from early or recent sample isolates (P = 0.8035). Interestingly, a significantly greater loss of RC was observed in the PI-resistant protease group (P = 0.0400). These results demonstrate that protease sequence diversification has not affected HIV-1 RC or protease robustness and indicate that proteases carrying PI resistance substitutions are less robust than naïve proteases.

scholarly journals An Integrative Bioinformatic Approach for Studying Escape Mutations in Human Immunodeficiency Virus Type 1 gag in the Pumwani Sex Worker Cohort

2007 ◽  
Vol 82 (4) ◽  
pp. 1980-1992 ◽  
Author(s):  
Harold O. Peters ◽  
Mark G. Mendoza ◽  
Rupert E. Capina ◽  
Ma Luo ◽  
Xiaojuan Mao ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Disease Progression ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Antigen Processing ◽  
Cd4 Counts ◽  
Immunodeficiency Virus ◽  
Proteasomal Cleavage ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) is able to evade the host cytotoxic T-lymphocyte (CTL) response through a variety of escape avenues. Epitopes that are presented to CTLs are first processed in the presenting cell in several steps, including proteasomal cleavage, transport to the endoplasmic reticulum, binding by the HLA molecule, and finally presentation to the T-cell receptor. An understanding of the potential of the virus to escape CTL responses can aid in designing an effective vaccine. To investigate such a potential, we analyzed HIV-1 gag from 468 HIV-1-positive Kenyan women by using several bioinformatic approaches that allowed the identification of positively selected amino acids in the HIV-1 gag region and study of the effects that these mutations could have on the various stages of antigen processing. Correlations between positively selected residues and mean CD4 counts also allowed study of the effect of mutation on HIV disease progression. A number of mutations that could create or destroy proteasomal cleavage sites or reduce binding affinity of the transport antigen processing protein, effectively hindering epitope presentation, were identified. Many mutations correlated with the presence of specific HLA alleles and with lower or higher CD4 counts. For instance, the mutation V190I in subtype A1-infected individuals is associated with HLA-B*5802 (P = 4.73 × 10−4), a rapid-progression allele according to other studies, and also to a decreased mean CD4 count (P = 0.019). Thus, V190I is a possible HLA escape mutant. This method classifies many positively selected mutations across the entire gag region according to their potential for immune escape and their effect on disease progression.

scholarly journals Relative roles of signals upstream of AAUAAA and promoter proximity in regulation of human immunodeficiency virus type 1 mRNA 3' end formation.

1992 ◽  
Vol 12 (12) ◽  
pp. 5555-5562 ◽  
Author(s):  
J D DeZazzo ◽  
J M Scott ◽  
M J Imperiale
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Dependent Manner ◽  
Immunodeficiency Virus ◽  
A Site ◽  
The Impact ◽  
Hiv 1 ◽  
Rna Levels

At least two mechanisms have been implicated in regulating poly(A) site use in human immunodeficiency virus type 1 (HIV-1): inhibition of basal signals within 500 nucleotides (nt) of the cap site, leading to specific suppression of the 5' poly(A) site, and stimulation of basal signals by long terminal repeat U3 sequences, leading to specific activation of the 3' poly(A) site. We determined the relative contributions of these mechanisms in a HeLa cell transcription/processing reaction and by transient transfection analysis. In vitro, the efficiency of basal signals is equivalent close to (270 nt) and far from (1,080 nt) the promoter and is stimulated at least 30-fold in both positions by upstream U3 sequences. In vivo, U3 sequences also enhance processing at both positions. There are two additional effects when the poly(A) site is close to the cap site: at least a 15-fold reduction in total RNA levels and a 5-fold decrease in relative levels of RNA processed at the HIV-1 site in constructs containing U3. Both effects are overcome by insertion of upstream splicing signals in an orientation-dependent manner. Splicing appears to influence poly(A)+ RNA levels by two distinct mechanisms: stabilizing nuclear transcripts and directly stimulating 3' end formation. It is proposed that upstream elements play major roles in regulating poly(A) site choice and in controlling the subsequent fate of polyadenylated RNA. The impact of these findings on mechanisms of mRNA biogenesis in the HIV-1 provirus is discussed.

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