Antiretroviral agents: Focus on Maraviroc for the Treatment of HIV-1-Infected Adults

2010 ◽  
Vol 2 ◽  
pp. CMT.S5420
Author(s):  
SL. Pett ◽  
S. Emery ◽  
AD. Kelleher ◽  
DA. Cooper
Keyword(s):  
Hiv Infection ◽  
Chemokine Receptors ◽  
Hiv Transmission ◽  
Hiv Therapy ◽  
Ccr5 Receptor ◽  
Tick Borne Encephalitis ◽  
Hiv Entry ◽  
Orally Bioavailable ◽  
Hiv Envelope ◽  
Hiv 1

Over a decade has passed since several groups identified the chemokine receptors CXCR4 and CCR5 as key co-receptors for HIV entry. CCR5 is more important in HIV transmission and during the early course of HIV infection. It is also apparent that protection from HIV infection is afforded to those lacking CCR5–-the so called delta-32 homozygotes; in those heterozygous for this mutation, an attenuated course of HIV-infection is observed. Provocatively, those with modified expression of CCR5 are physiologically normal with the exception of poorer outcomes with some of the viral encephalitides specifically West Nile virus and Tick Borne encephalitis. The small molecule, orally-bioavailable CCR5 receptor antagonists, including, maraviroc (MVC), are allosteric inhibitors that lock the CCR5 receptor into a conformation such that the receptor is not able to bind HIV envelope protein; the molecules also variably block intracellular signalling induced by different receptor-binding chemokines. The aims of this review on the CCR5 receptor inhibitors are to summarise information relevant to treatment in individuals with HIV-1 infection. Data from the licensing studies, the side-effect profile and putative long-term risks of CCR5 receptor inhibitor exposure, tropism testing and mechanisms of resistance will be reviewed. The potential for using this class of agent as an immunomodulating agent will be detailed. Given that MVC is the only licensed drug in this class at present and reflecting the greater body of work describing this agent, the majority of information in this review relates to MVC. Last, the authors propose the place of MVC in the hierarchy of HIV therapy and future opportunities for research.

scholarly journals Structure/Function Studies Involving the V3 Region of the HIV-1 Envelope Delineate Multiple Factors That Affect Neutralization Sensitivity

2015 ◽  
Vol 90 (2) ◽  
pp. 636-649 ◽  
Author(s):  
Susan Zolla-Pazner ◽  
Sandra Sharpe Cohen ◽  
David Boyd ◽  
Xiang-Peng Kong ◽  
Michael Seaman ◽  
...  
Keyword(s):  
Amino Acid ◽  
Hiv Infection ◽  
Chemokine Receptors ◽  
Variable Region ◽  
Single Amino Acid ◽  
V3 Loop ◽  
Infection Rates ◽  
Neutralization Sensitivity ◽  
The Stability ◽  
Hiv 1

ABSTRACTAntibodies (Abs) specific for the V3 loop of the HIV-1 gp120 envelope neutralize most tier 1 and many tier 2 viruses and are present in essentially all HIV-infected individuals as well as immunized humans and animals. Vaccine-induced V3 Abs are associated with reduced HIV infection rates in humans and affect the nature of transmitted viruses in infected vaccinees, despite the fact that V3 is often occluded in the envelope trimer. Here, we link structural and experimental data showing how conformational alterations of the envelope trimer render viruses exceptionally sensitive to V3 Abs. The experiments interrogated the neutralization sensitivity of pseudoviruses with single amino acid mutations in various regions of gp120 that were predicted to alter packing of the V3 loop in the Env trimer. The results indicate that the V3 loop is metastable in the envelope trimer on the virion surface, flickering between states in which V3 is either occluded or available for binding to chemokine receptors (leading to infection) and to V3 Abs (leading to virus neutralization). The spring-loaded V3 in the envelope trimer is easily released by disruption of the stability of the V3 pocket in the unliganded trimer or disruption of favorable V3/pocket interactions. Formation of the V3 pocket requires appropriate positioning of the V1V2 domain, which is, in turn, dependent on the conformation of the bridging sheet and on the stability of the V1V2 B-C strand-connecting loop.IMPORTANCEThe levels of antibodies to the third variable region (V3) of the HIV envelope protein correlate with reduced HIV infection rates. Previous studies showed that V3 is often occluded, as it sits in a pocket of the envelope trimer on the surface of virions; however, the trimer is flexible, allowing occluded portions of the envelope (like V3) to flicker into an exposed position that binds antibodies. Here we provide a systematic interrogation of mechanisms by which single amino acid changes in various regions of gp120 (i) render viruses sensitive to neutralization by V3 antibodies, (ii) result in altered packing of the V3 loop, and (iii) activate an open conformation that exposes V3 to the effects of V3 Abs. Taken together, these and previous studies explain how V3 antibodies can protect against HIV-1 infection and why they should be one of the targets of vaccine-induced antibodies.

scholarly journals Effect of HIV Envelope Vaccination on the Subsequent Antibody Response to HIV Infection

mSphere ◽  
2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Zanele Ditse ◽  
Nonhlanhla N. Mkhize ◽  
Michael Yin ◽  
Michael Keefer ◽  
David C. Montefiori ◽  
...  
Keyword(s):  
Immune Responses ◽  
Hiv Infection ◽  
South African ◽  
Phase 1 ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Tier 2 ◽  
Subtype C ◽  
Hiv Envelope ◽  
Hiv 1

ABSTRACT Analysis of breakthrough HIV-1 infections could elucidate whether prior vaccination primes relevant immune responses. Here, we measured HIV-specific antibody responses in 14 South African volunteers who acquired HIV infection after participating in phase 1/2 trials of envelope-containing immunogens. Serum samples were collected annually following HIV-1 infection from participants in trials HVTN 073 (subtype C, DNA/MVA, phase 1 trial, n = 1), HVTN 086 (subtype C, DNA/MVA/gp140 protein, phase 1 trial, n = 2), and HVTN 204 (multisubtype, DNA/adenovirus serotype 5 [Ad5], phase 2 trial, n = 7) and 4 placebo recipients. Binding and neutralizing antibody responses to Env proteins and peptides were determined pre- and post-HIV infection using an enzyme-linked immunosorbent assay and the TZM-bl cell neutralization assay, respectively. HIV-infected South African individuals served as unvaccinated controls. Binding antibodies to gp41, V3, V2, the membrane-proximal external region (MPER), and the CD4 binding site were detected from the first year of HIV-1 subtype C infection, and the levels were similar in vaccinated and placebo recipients. Neutralizing antibody responses against tier 1A viruses were detected in all participants, with the highest titers being to a subtype C virus, MW965.26. No responses were observed just prior to infection, indicating that vaccine-primed HIV-specific antibodies had waned. Sporadic neutralization activity against tier 2 isolates was observed after 2 to 3 years of HIV infection, but these responses were similar in the vaccinated and placebo groups as well as the unvaccinated controls. Our data suggest that prior vaccination with these immunogens did not alter the antibody responses to HIV-1 infection, nor did it accelerate the development of HIV neutralization breadth. IMPORTANCE There is a wealth of information on HIV-specific vaccine-induced immune responses among HIV-uninfected participants; however, data on immune responses among participants who acquire HIV after vaccination are limited. Here we show that HIV-specific binding antibody responses in individuals with breakthrough HIV infections were not affected by prior vaccination with HIV envelope-containing immunogens. We also found that these vectored vaccines did not prime tier 2 virus-neutralizing antibody responses, which are thought to be required for prevention against HIV acquisition, or accelerate the development of neutralization breadth. Although this study is limited, such studies can provide insights into whether vaccine-elicited antibody responses are boosted by HIV infection to acquire broader neutralizing activity, which may help to identify antigens relevant to the design of more effective vaccines.

Interferon-γ Upregulates CCR5 Expression in Cord and Adult Blood Mononuclear Phagocytes

Blood ◽  
1999 ◽  
Vol 93 (4) ◽  
pp. 1137-1144 ◽  
Author(s):  
Deepa Hariharan ◽  
Steven D. Douglas ◽  
Benhur Lee ◽  
Jian-Ping Lai ◽  
Donald E. Campbell ◽  
...  
Keyword(s):  
Cell Surface ◽  
Hiv Infection ◽  
Chemokine Receptors ◽  
Surface Expression ◽  
Interferon Γ ◽  
Mononuclear Phagocytes ◽  
Cell Surface Expression ◽  
Ccr5 Expression ◽  
Hiv Entry ◽  
Ifn Γ

Abstract The C-C chemokine receptors CCR5 and CCR3 are fusion coreceptors for human immunodeficiency virus (HIV) entry into macrophages. The regulation of their expression influences infectivity by HIV. We report here that interferon-γ (IFN-γ) a cytokine that has bidirectional effects on HIV infection of macrophages, significantly upregulated CCR5 and CCR3 cell surface expression in human mononuclear phagocytes isolated from placental cord blood and adult peripheral blood. Monocytes treated with IFN-γ showed increased chemotaxis to the CCR5 ligands macrophage inflammatory protein-1 (MIP-1) and MIP-1β, confirming the functional relevance of IFN-γ–induced CCR5 expression. However, IFN-γ suppressed HIV entry into macrophages. Interestingly, we demonstrated that IFN-γ inhibited cell surface expression of CD4, the major receptor for HIV. This finding may explain the suppressive effect of IFN-γ on HIV entry into macrophages, despite its enhancing effect on the expression of CCR5 and CCR3 by these cells. In addition, IFN-γ–induced secretion of C-C chemokines (RANTES, MIP-1, and MIP-1β) by mononuclear phagocytes may also suppress HIV entry into macrophages. These data provide further evidence for cytokine-mediated regulation of CCR5 expression and are consistent with a novel paradigm in which cytokines regulate HIV infection and leukocyte migration by reciprocal and opposing effects on the expression of CD4 and chemokine receptors.

Human Immunodeficiency Virus (HIV)-Resistant CD4+ UT-7 Megakaryocytic Human Cell Line Becomes Highly HIV-1 and HIV-2 Susceptible Upon CXCR4 Transfection: Induction of Cell Differentiation by HIV-1 Infection

Blood ◽  
1997 ◽  
Vol 89 (8) ◽  
pp. 2670-2678 ◽  
Author(s):  
Marta Baiocchi ◽  
Eleonora Olivetta ◽  
Cristiana Chelucci ◽  
Anna Claudia Santarcangelo ◽  
Roberta Bona ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Hiv Infection ◽  
Cell Line ◽  
Viral Entry ◽  
Human Cell Line ◽  
Immunodeficiency Virus ◽  
Hiv Entry ◽  
Stromal Cell Derived Factor ◽  
Hiv 1

Abstract Recent findings have shown that the expression of the seven trans-membrane G-protein–coupled CXCR4 (the receptor for the stromal cell-derived factor [SDF]-1 chemokine) is necessary for the entry of T-lymphotropic human immunodeficiency virus (HIV) strains, acting as a coreceptor of the CD4 molecule. In the human system, the role of CXCR4 in HIV infection has been determined through env-mediated cell fusion assays and confirmed by blocking viral entry in CD4+/CXCR4+ cells by SDF-1 pretreatment. We observed that the human megakaryoblastic CD4+ UT-7 cell line fails to express CXCR4 RNA and is fully resistant to HIV entry. Transfection of an expression vector containing the CXCR4 c-DNA rendered UT-7 cells readily infectable by different T-lymphotropic syncytium-inducing HIV-1 and HIV-2 isolates. Interestingly, HIV-1 infection of CXCR4 expressing UT-7 cells (named UT-7/fus) induces the formation of polynucleated cells through a process highly reminiscent of megakaryocytic differentiation and maturation. On the contrary, no morphologic changes were observed in HIV-2–infected UT-7/fus cells. These findings further strengthen the role of CXCR4 as a molecule necessary for the replication of T-lymphotropic HIV-1 and HIV-2 isolates and provide a useful model to study the functional role of CD4 coreceptors in HIV infection.

scholarly journals Overview of genotypic and clinical profiles of human immunodeficiency virus type 1-infected children in Rio de Janeiro, Brazil

2004 ◽  
Vol 76 (4) ◽  
pp. 727-741 ◽  
Author(s):  
Elizabeth S. Machado ◽  
John S. Lambert ◽  
Adriana O. Afonso ◽  
Silvia M. Cunha ◽  
Ricardo H. Oliveira ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Rio De Janeiro ◽  
Hiv Transmission ◽  
Clinical Laboratory ◽  
Adult Population ◽  
Developed Countries ◽  
Pediatric Hiv ◽  
Resistance Mutations ◽  
Drug Naïve ◽  
Hiv 1

Although mother-to-child HIV transmission prevention has slowed down pediatric HIV infection in developed countries, large numbers of infants still become infected in developing nations. Data on pediatric HIV infection is however largely scarce. In this study, we have overviewed clinical, laboratory and genotypic data from a large cohort of HIV-infected infants regularly followed at two pediatric HIV outpatient clinics in Rio de Janeiro, Brazil. Children on antiretroviral therapy, as well as drug-naïve, newly diagnosed infants were analyzed. Prevalence of drug resistance mutations, as well as immunological and virological responses to therapy were evaluated. Additionally, HIV-1 subtype frequencies and their distribution over the course of the epidemic were studied. We have found a high prevalence of mutations among ARV-experienced children, whereas mutations were absent in the drug-naïve group. Despite the high levels of resistance among treated infants, an important improvement of their immunological status was observed. HIV-1 subtype distribution followed the trends of the adult population, with the appearance of non-B subtypes and recombinant forms after 1990. To our knowledge, this is the largest pediatric cohort ever analyzed in Brazil, and the data provided is of paramount importance to a better understanding of HIV/AIDS evolution in pediatric settings.

scholarly journals Microglia Express CCR5, CXCR4, and CCR3, but of These, CCR5 Is the Principal Coreceptor for Human Immunodeficiency Virus Type 1 Dementia Isolates

1999 ◽  
Vol 73 (1) ◽  
pp. 205-213 ◽  
Author(s):  
Andrew V. Albright ◽  
Joseph T. C. Shieh ◽  
Takayuki Itoh ◽  
Benhur Lee ◽  
David Pleasure ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Chemokine Receptors ◽  
Calcium Flux ◽  
Human Adult ◽  
Immunodeficiency Virus ◽  
The Central Nervous System ◽  
Hiv Entry ◽  
G Protein Coupled ◽  
Hiv 1

ABSTRACT Microglia are the main human immunodeficiency virus (HIV) reservoir in the central nervous system and most likely play a major role in the development of HIV dementia (HIVD). To characterize human adult microglial chemokine receptors, we analyzed the expression and calcium signaling of CCR5, CCR3, and CXCR4 and their roles in HIV entry. Microglia expressed higher levels of CCR5 than of either CCR3 or CXCR4. Of these three chemokine receptors, only CCR5 and CXCR4 were able to transduce a signal in microglia in response to their respective ligands, MIP-1β and SDF-1α, as recorded by single-cell calcium flux experiments. We also found that CCR5 is the predominant coreceptor used for infection of human adult microglia by the HIV type 1 dementia isolates HIV-1DS-br, HIV-1RC-br, and HIV-1YU-2, since the anti-CCR5 antibody 2D7 was able to dramatically inhibit microglial infection by both wild-type and single-round luciferase pseudotype reporter viruses. Anti-CCR3 (7B11) and anti-CXCR4 (12G5) antibodies had little or no effect on infection. Last, we found that virus pseudotyped with the DS-br and RC-br envelopes can infect cells transfected with CD4 in conjunction with the G-protein-coupled receptors APJ, CCR8, and GPR15, which have been previously implicated in HIV entry.

CCR5 Antagonists: Host-Targeted Antivirals for the Treatment of HIV Infection

2005 ◽  
Vol 16 (6) ◽  
pp. 339-354 ◽  
Author(s):  
Mike Westby ◽  
Elna van der Ryst
Keyword(s):  
Hiv Infection ◽  
Small Molecule ◽  
Chemokine Receptors ◽  
Ccr5 Gene ◽  
Sexually Transmitted ◽  
New Class ◽  
Ccr5 Antagonists ◽  
Resistance To Infection ◽  
Plasma Half Life ◽  
Hiv 1

The human chemokine receptors, CCR5 and CXCR4, are potential host targets for exogenous, small-molecule antagonists for the inhibition of HIV-1 infection. HIV-1 strains can be categorised by co-receptor tropism — their ability to utilise CCR5 (CCR5-tropic), CXCR4 (CXCR4-tropic) or both (dual-tropic) as a co-receptor for entry into susceptible cells. CCR5 may be the more suitable co-receptor target for small-molecule antagonists because a natural deletion in the CCR5 gene preventing its expression on the cell surface is not associated with any obvious phenotype, but can confer resistance to infection by CCR5-tropic strains — the most frequently sexually-transmitted strains. The current leading CCR5 antagonists in clinical development include maraviroc (UK-427,857, Pfizer), aplaviroc (873140, GlaxoSmithKline) and vicriviroc (SCH-D, Schering-Plough), which have demonstrated efficacy and tolerability in HIV-infected patients. Pharmacodynamic data also suggest that these compounds have a long plasma half-life and/or prolonged CCR5 occupancy, which may explain the delay in viral rebound observed following compound withdrawal in short-term monotherapy studies. A switch from CCR5 to CXCR4 tropism occurs spontaneously in approximately 50% of HIV-infected patients and has been associated with, but is not required for, disease progression. The possibility of a co-receptor tropism switch occurring under selection pressure by CCR5 antagonists is discussed. The completion of ongoing Phase IIb/III studies of maraviroc, aplaviroc and vicriviroc will provide further insight into co-receptor tropism, HIV pathogenesis and the suitability of CCR5 antagonists as a potent new class of antivirals for the treatment of HIV infection.

scholarly journals Immunogenicity and safety of rapid scheme vaccination against tick-borne encephalitis in HIV-1 infected persons

2021 ◽  
Vol 149 ◽  
Author(s):  
D. Jilich ◽  
M. Maly ◽  
P. Kosina ◽  
L. Fleischhans ◽  
L. Machala
Keyword(s):  
Adverse Events ◽  
Hiv Infection ◽  
Small Proportion ◽  
Seroprotection Rate ◽  
Serious Adverse Events ◽  
Tick Borne Encephalitis ◽  
Specific Igg ◽  
Vector Borne ◽  
Endemic Areas ◽  
Hiv 1

Abstract Tick-borne encephalitis (TBE) is a vector-borne infection associated with a variety of potentially serious complications and sequelae. Vaccination against TBE is strongly recommended for people living in endemic areas. There are two TBE vaccination schemes – standard and rapid – which differ in the onset of protection. With vaccination in a rapid schedule, protection starts as early as 4 weeks after the first dose and is therefore especially recommended for non-immune individuals travelling to endemic areas. Both schemes work reliably in immunocompetent individuals, but only little is known about how TBE vaccination works in people with HIV infection. Our aim was to assess the immunogenicity and safety of the rapid scheme of TBE vaccination in HIV-1 infected individuals. Concentrations of TBE-specific IgG > 126 VIEU/ml were considered protective. The seroprotection rate was 35.7% on day 28 and 39.3% on day 60. There were no differences between responders and non-responders in baseline and nadir CD4 + T lymphocytes. No serious adverse events were observed after vaccination. The immunogenicity of the TBE vaccination was unsatisfactory in our study and early protection was only achieved in a small proportion of vaccinees. Therefore, TBE vaccination with the rapid scheme cannot be recommended for HIV-1 infected individuals.

Herpes and HIV infection—has the time come to act?

Sexual Health ◽  
2006 ◽  
Vol 3 (2) ◽  
pp. 67 ◽  
Author(s):  
Darren B. Russell
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Hiv Infection ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Hiv Transmission ◽  
Increased Risk ◽  
Simplex Virus ◽  
Hiv 1

It has been known for some years that the ulcerative and inflammatory STIs lead to an increased risk of HIV transmission. In particular, there is a two- to four-fold increased risk of HIV-1 acquisition associated with prevalent herpes simplex virus type 2. The challenges are discussed herein.

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