This review discusses recent progress in the development of anti-HIV agents, with emphasis on small molecule HIV-1 entry inhibitors. The entry inhibitors primarily target HIV-1 envelope glycoproteins or the cellular receptors, CD4 and chemokine receptors. Two of the entry inhibitors, enfuvirtide and maraviroc, have been approved by the US FDA for AIDS therapy. The drug resistance associated with some of the entry inhibitors will also be discussed.
Anti-HIV Agents ; chemistry ; pharmacology ; therapeutic use ; CCR5 Receptor Antagonists ; CD4 Antigens ; drug effects ; Cyclohexanes ; pharmacology ; therapeutic use ; Drug Resistance, Viral ; HIV Envelope Protein gp120 ; pharmacology ; HIV Envelope Protein gp41 ; pharmacology ; therapeutic use ; HIV Fusion Inhibitors ; chemistry ; pharmacology ; therapeutic use ; HIV Infections ; drug therapy ; HIV-1 ; drug effects ; Humans ; Molecular Structure ; Peptide Fragments ; pharmacology ; therapeutic use ; Receptors, CCR5 ; physiology ; Receptors, CXCR4 ; antagonists & inhibitors ; Receptors, Chemokine ; drug effects ; Triazoles ; pharmacology ; therapeutic use

Background: HIV (human immunodeficiency virus) is the virus that causes AIDS. This virus is passed from one person to another through blood-to-blood and sexual contact. In addition, infected pregnant women can pass HIV to their baby during pregnancy or delivery, as well as through breast-feeding. Objectives:To study the CCR5- 32 and SDF 1-3 A allelic frequence in the HIV -1 infected mothers and their children. Subjects and method: Amplificated on CCR5 and SDF1 gene by PCR and restriction of this fragment length polymorphisme (RLFP) assay for detection of the mutated gene by EcoR1 and Hpall. Results: No mutation of CCR5 was found but only mutation identified at the SDF1 gene. Mutation identified at the SDF1 gene of the mother was: homozygote 2.7% (accounted for 2/37 cases), heterozygote 40.54% (accounted for 15/37 cases) and at the children: homozygote 5.4% (accounted for 1/37 cases), heterozygote 45.95% (accounted for 17/37 cases). The CCR5 chemokin receptor is a co-receptor for M trofic HIV-1 strains, which predominate in the early stage of the HIV disease and SDF-1 natural ligand for the CXCR4 reception. The mutation of these genes protect from HIV-1 infection (slow progression).\r\n', u'Conclusion: It\u2019s necessary to find the mutation of CCR5 and CCR2b related the progression of HIV patients. \r\n', u'
HIV-1/ metabolism ; Receptors ; CCR5

Aminoquinolines ; pharmacology ; Anti-HIV Agents ; pharmacology ; Benzimidazoles ; pharmacology ; CCR5 Receptor Antagonists ; CD4 Antigens ; metabolism ; Cyclohexanes ; pharmacology ; HIV-1 ; pathogenicity ; physiology ; Heterocyclic Compounds ; pharmacology ; Heterocyclic Compounds, 1-Ring ; Humans ; Maraviroc ; Piperazines ; pharmacology ; Pyrimidines ; pharmacology ; Receptors, CCR5 ; metabolism ; Receptors, CXCR4 ; antagonists & inhibitors ; metabolism ; T-Lymphocytes ; virology ; Triazoles ; pharmacology ; Viral Tropism

OBJECTIVETo study the quantity of anti-R7V in individuals infected with HIV and AIDS patients and its relation with the progression of disease.

METHODSELISA and precipitation and other methods were used to investigate the quantity of anti-R7V in asymptomatic long-term survivors and AIDS patients.

RESULTSPositive rate and quantity of anti-R7V were higher in the HIV active ones and AIDS. It showed that the quantity and positive rate of anti-R7V were rather high in dissolving test.

CONCLUSIONSIt is strong suggestion for anti-R7V to obstruct the replication of virus by interfering the connection between HIV with CCR5 or CXCR4 and so it impossible HIV entering to CD4+ T cells.

Acquired Immunodeficiency Syndrome ; immunology ; Adolescent ; Adult ; Aged ; Child ; Female ; Follow-Up Studies ; HIV Antibodies ; blood ; HIV Infections ; immunology ; HIV Long-Term Survivors ; HIV-1 ; immunology ; Humans ; Male ; Middle Aged ; Receptors, CCR5 ; physiology ; Receptors, CXCR4 ; physiology

Adult ; CD4 Lymphocyte Count ; Cell Line, Tumor ; Female ; HIV-1 ; classification ; physiology ; Humans ; Male ; Middle Aged ; Receptors, CCR5 ; physiology ; Receptors, CXCR4 ; physiology ; Recombination, Genetic ; Viral Load

OBJECTIVETo investigate HIV-1 co-receptor usage in patients experienced anti-retroviral therapy (ART) in Anhui and Henan province of China.

METHODSA total of 45 HIV-1 infected individuals who have experienced ART and 109 un-experienced ART patients from Anhui and Henan province, which were called as treatment group and treatment-negative group, were selected as study subjects. HIV-1 strains were isolated from peripheral blood mononuclear cells of whole blood from patients. HIV-1 p24 in the culture supernatant was measured using a commercial enzyme-linked immunosorbent assay (ELISA) kit. HIV-1 co-receptor usage was identified using Ghost cell lines expressing CD4 and the chemokine receptor CCR5 or CXCR4.

RESULTSAmong 45 HIV strains from the treatment group, 22 (48.9%) strains used CCR5 as a co-receptor (R5 tropic strain), 21 (46.7%) strains used CXCR4/CCR5 as a co-receptor (X4/R5 duel tropic strain), and 2 (4.4%) used only CXCR4 as a co-receptor (X4 tropic strain). In 109 strains from treatment-negative group, 96 (88.1%) strains used CCR5 as a co-receptor (R5 tropic strain), 13 (11.9%) strains used CCR5/CXCR4 as a co-receptor use (X4/R5 strain). A significant difference was found between two groups in X4 co-receptor usages (χ(2) = 27.30, P < 0.05). Furthermore, after treated with AZT + DDI + NVP, the HIV-1 CXC4/CCR5 utilization was 59.09% (13/22), meanwhile after treated with D4T + DDI + NVP, the HIV-1 CXC4/CCR5 utilization was 43.48% (10/23), which the difference was not statistical significant (χ(2) = 1.10, P = 0.30).

CONCLUSIONHIV-1 CXCR4/CCR5 co-receptor utilization was higher in ART patients than treatment-negative patients.

Acquired Immunodeficiency Syndrome ; drug therapy ; metabolism ; Adult ; Aged ; Antiviral Agents ; therapeutic use ; Cells, Cultured ; Female ; HIV-1 ; isolation & purification ; Humans ; Male ; Middle Aged ; Receptors, CCR5 ; metabolism ; Receptors, CXCR4 ; metabolism ; Receptors, HIV ; metabolism

OBJECTIVETo investigate the coreceptors CCR5 and CXCR4 expressions on the peripheral blood T lymphocytes in HIV/AIDS patients, with an analysis of their clinical value.

METHODSThirty HIV/AIDS patients and 16 normal controls were selected and flow-cytometry was used to detect the coreceptors CCR5 and CXCR4 expressions in whole blood samples taken from the patients and controls. An analysis was made of the correlation of the coreceptor expression with CD4 T cell counts and the activation of CD4+/ CD8+ T cells (HLA-DR+/CD38+).

RESULTSThe CCR5 expression on CD8+ lymphocytes and the CXCR4 expression on the CD4+/ CD8+ T lymphocytes of the HIV/AIDS group were higher than those of the normal controls (P < 0.01). The CCR5 and CXCR4 expressions on the CD4+/CD8+ T lymphocytes of the HIV/AIDS patients was significantly correlated with the activation of CD4+/CD8+ T cells (HLA-DR+/CD38+) (P < 0.05).

CONCLUSIONThe expressions of CCR5 and CXCR4 are significantly correlated with the immune system reaction to HIV and the disease progression in HIV infected patients.

Acquired Immunodeficiency Syndrome ; blood ; Adolescent ; Adult ; Case-Control Studies ; Child ; Child, Preschool ; Female ; HIV Infections ; blood ; Humans ; Male ; Middle Aged ; Receptors, CCR5 ; biosynthesis ; Receptors, CXCR4 ; biosynthesis ; T-Lymphocytes ; metabolism

OBJECTIVETo measure CCR5 and CXCR4 chemokine receptor expression on CD4 and CD8 T cells in HIV-1 infection and to relate levels to the distribution of CD45RO memory and CD45RA-naive subsets after effective HAART.

METHODSFour-color cytofluorometry with appropriate conjugated monoclonal antibodies (mAbs) was performed to define CD45RA and CD45RO subsets of CD4 and CD8 T cells and measure the expression of CCR5, CXCR4 in blood from 43 received HAART patients and 5 non-treated HIV and 13 healthy controls.

RESULTSThe levels of CCR5 and CXCR4 on CD4 and CD8 T cells and their CD45RO/CD45RA subsets in HIV-1-infected patients had not any statistical significance than that on control subjects and effective HAART could adjust the expression on T cells.

CONCLUSIONCXCR4/CCR5 plays an important role in the progress of HIV-1 infection. The most favorable condition for treatment should be initiated before stage B.

Acquired Immunodeficiency Syndrome ; drug therapy ; immunology ; Antiretroviral Therapy, Highly Active ; CD4-Positive T-Lymphocytes ; chemistry ; CD8-Positive T-Lymphocytes ; chemistry ; HIV-1 ; Humans ; Receptors, CCR5 ; blood ; drug effects ; Receptors, CXCR4 ; blood ; drug effects

OBJECTIVEAlthough HIV-1 infection is prevalent in many regions in China, it remains largely unknown on the biological characteristics of dominant circulating isolates. This study was designed to isolate the circulating viral strains from different prevalent regions and to characterize their biological properties and neutralization sensitivity.

METHODSPrimary viruses were isolated from fresh PBMCs using the traditional co-culture method and their capacity of inducing syncytium was tested in MT-2 cells. Meanwhile, their coreceptor usage was determined with two cell lines: Magi and GHOST (3) stably expressing CD4 and the chemokine receptor CCR5 or CXCR4. Furthermore, the sensitivity of these viruses to neutralization by HIV-1-infected patients' plasma which were highly active to neutralize SF33 strain, was quantified in GHOST cell-based neutralization assay.

RESULTSSix primary viral strains were isolated from 4 separated regions. Isolates LTG0213, LTG0214 and XVS032691 induced syncytia in MT-2 cells, and used CXCR4 as coreceptor. Isolates XJN0021, XJN0091, or SHXDC0041 did not induce syncytia, and used CCR5 as coreceptor. Overall neutralization sensitivity differed among four representative strains: HIV-1 XVS032691 > LTG0214 >XJN0091 approximately SHXDC0041.

CONCLUSIONThe neutralization sensitivity of HIV isolates is linked with the phenotype of isolates, in which syncytium-inducing (SI) or CXCR4-tropic (X4) viruses are more easily neutralized than non-syncytium-inducing (NSI) or CCR5-tropic (R5) viruses. The genetic subtypes based on the phylogeny of env sequences are not classical neutralization serotypes.

CD4-Positive T-Lymphocytes ; metabolism ; Cell Line ; Cells, Cultured ; Chemokines ; genetics ; immunology ; China ; Coculture Techniques ; methods ; Giant Cells ; ultrastructure ; virology ; HIV Infections ; virology ; HIV Seropositivity ; genetics ; immunology ; HIV-1 ; immunology ; isolation & purification ; physiology ; Humans ; Neutralization Tests ; Receptors, CCR5 ; metabolism ; Receptors, CXCR4 ; metabolism ; Virus Replication

CCR5, a membrane protein on cell surface, is a member of the G protein-coupled receptor superfamily and one of the major co-receptors for HIV-1 infection. The roles of CCR5 in HIV-1 infection have been elucidated since 1996. Because of the biological nature of CCR5, it has became a molecular target for the novel drugs against HIV-1. Antagonists for CCR5 could be grouped as following, chemokine derivatives, small molecule non-peptide compounds, monoclonal antibodies and peptides. The latest progress in this field is reviewed in this article.
Anti-HIV Agents ; pharmacology ; Antibodies, Monoclonal ; CCR5 Receptor Antagonists ; Drug Design ; HIV Infections ; metabolism ; HIV-1 ; drug effects ; Receptors, CCR5 ; drug effects ; Receptors, Chemokine ; drug effects