A role for cell migration in the sexual transmission of HIV-1?

The issue of how human immunodeficiency virus-1 (HIV-1) enters the body following sexual contact has been the subject of considerable controversy. Several possible routes for the initial infection have been suggested [1-6], including the possibility that the transmission is mediated by HIV-1-infected lymphocytes or macrophages in serum and female genital tract secretions, rather than by free virus. We recently reported that HIV-1-infected, activated primary monocytes can migrate between epithelial cells grown in confluent monolayer cultures in vitro [7]. We report here on experiments carried out in mice to test the hypothesis that mononuclear blood cells are capable of migrating through intact epithelia, and thus of carrying a virus into an animal. We placed double-stained, activated mononuclear blood cells into the vaginas of mice; four hours later, numerous double-stained cells were observed in the connective tissue beneath the vaginal epithelium and the iliac lymph nodes of the experimental mice. We speculate that such migration may be involved in the sexual transmission of HIV-1.     

HIV-1-induced cell fusion is mediated by multiple regions within both the viral envelope and the CCR-5 co-receptor

Although the human hCCR-5 chemokine receptor can serve as a co-receptor for both M-tropic (ADA and BaL) and dual-tropic (89.6) strains of human immunodeficiency virus type 1 (HIV-1), the closely related mouse mCCR-5 homolog is inactive. We used chimeric hCCR-5-mCCR-5 receptor molecules to examine the functional importance of the three extracellular domains of hCCR-5 that differ in sequence from their mCCR-5 equivalents. While this analysis revealed that all three of these extracellular domains could participate in the functional interaction with HIV-1 envelope, clear differences were observed when different HIV-1 strains were analyzed. Thus, while the ADA HIV-1 isolate could effectively utilize chimeric human-mouse CCR-5 chimeras containing any single human extracellular domain, the BaL isolate required any two human extracellular sequences while the 89.6 isolate would only interact effectively with chimeras containing all three human extracellular sequences. Further analysis using hybrid HIV-1 envelope proteins showed that the difference in co-receptor specificity displayed by the ADA and BaL isolates was due partly to a single amino acid change in the V3 loop, although this interaction was clearly also modulated by other envelope domains. Overall, these data indicate that the interaction between HIV-1 envelope and CCR-5 is not only complex but also subject to marked, HIV-1 isolate-dependent variation.     

Absence of hepatitis C virus transmission but frequent transmission of HIV-1 from sexual contact with doubly-infected individuals

Reported here is a case of an inferior mesenteric varix demonstrated by 99mTc-red blood cell (RBC) scintigraphy performed for gastrointestinal bleeding in a 47-year-old man. It was shaped like a question mark ranging from the left upper abdomen to the pelvis. This is the first report of scintigraphic recognition of an inferior mesenteric varix.     

CCR5 chemokine receptor genotype frequencies among Puerto Rican HIV-1-seropositive individuals

Some individuals remain uninfected by human immunodeficiency virus type 1 (HIV-1), despite multiple sexual contacts with subjects with confirmed HIV-1 infection. Several studies have confirmed that individuals who are homozygous for a 32 base pair (bp) deletion mutation in the chemokine receptor gene CCR5, designated as delta 32/ delta 32, are protected against HIV-1 infection. Heterozygotes of the same chemokine receptor deletion mutation are, however, not protected from acquiring HIV-1 infection but seemingly have slower progression to acquired immunodeficiency syndromes (AIDS). Genotype frequencies of the delta 32 CCR5 mutation vary markedly among different ethnic groups; heterozygosity is found in approximately 15% of Caucasians, about 5-7% of Hispanics and African Americans and 1% or less of Asians. The ethnic background of Puerto Ricans is highly complex and usually includes admixture of Caucasian, Caribbean Indian and African traits to a varying extent. This study was conducted to examine the frequencies of the delta 32 CCR5 mutation among Puerto Ricans who are infected with HIV-1. Samples were received from different geographical regions of the island. Of 377 samples tested, 94.2% were wild type (non-deletion mutant) homozygotes, 5.8% were delta 32 CCR5 heterozygotes, and none were delta 32 CCR5 homozygotes. The incidence of CCR5 delta 32/w heterozygous mutation among Puerto Ricans seems to be somewhat lower than what was reported with US Hispanics. Some age and gender associated bias of the mutation frequency were observed with the study population, the reason for which is unclear at present.     

Cloning and characterization of a novel murine beta chemokine receptor, D6. Comparison to three other related macrophage inflammatory protein-1alpha receptors, CCR-1, CCR-3, and CCR-5

The beta-chemokine macrophage inflammatory protein-1alpha (MIP-1alpha) is chemotactic for many hemopoietic cell types and can inhibit hemopoietic stem cell (HSC) proliferation, effects mediated through G-protein coupled heptahelical receptors. We have isolated cDNAs for seven chemokine receptors, CCR-1 to -5, MIP-1alphaRL1, and a novel cDNA, D6. Chinese hamster ovary cells expressing CCR-1, -3, -5, and D6 bound 125I-murine MIP-1alpha: the order of affinity was D6 > CCR-5 > CCR-1 > CCR-3. Each bound a distinct subset of other beta-chemokines: the order of competition for 125I-murine MIP-1alpha on D6 was murine MIP-1alpha > human and murine MIP-1beta > human RANTES approximately JE > human MCP-3 > human MCP-1. Human MIP-1alpha and the alpha-chemokines did not compete. Like other chemokine receptors, D6 induced transient increases in [Ca2+] in HEK 293 cells upon ligand binding. D6 mRNA was abundant in lung and detectable in many other tissues. Bone marrow cell fractionation demonstrated T-cell and macrophage/monocyte expression of D6, and CCR-1, -3, and -5. Moreover, we could detect expression of CCR-3, CCR-5, and to a greater extent D6 in a cell population enriched for HSCs. Thus, we have characterized four murine beta chemokine receptors that are likely involved in mediating the pro-inflammatory functions of MIP-1alpha and other chemokines, and we present D6, CCR-3, and CCR-5 as candidate receptors in MIP-1alpha-induced HSC inhibition.     

Vertical transmission of HIV-1 infection. Diagnosis and prevention

With an increase in the number of women of childbearing age being infected with HIV-1, the incidence of pediatric AIDS is rising precipitously. Therefore, it is necessary to identify the risks and the potential preventive methods that may be effective in decreasing the transmission from mother to child, i.e., vertical transmission. Administration of zidovudine has been demonstrated to significantly lower the rate of vertical transmission. Passive and active vaccination may also be useful in diminishing the transmission rate. Likewise, methods which provide a rapid and predictive measurement of the likelihood of vertical transmission, such as qualitative and quantitative differences in anti-HIV-1 maternal antibodies between transmitters and nontransmitters, have potential clinical utility.     

The role of the oral environment in HIV-1 transmission

Human immunodeficiency virus type 1, or HIV-1, is infrequently transmitted through the mouth, unlike other mucosal sites. Factors such as low salivary viral titers, low numbers of CD4-positive target cells, anti-HIV antibodies and endogenous salivary antiviral factors work in concert to protect oral tissues from infection and reduce the risk of viral transmission through salivary secretions. This review summarizes the various factors thought to influence oral transmission HIV-1, focusing on the mucosal protein secretory leukocyte protease inhibitor, or SLPI.     

Treatment history and baseline viral load, but not viral tropism or CCR-5 genotype, influence prolonged antiviral efficacy of highly active antiretroviral treatment

BACKGROUND: The efficacy of highly active antiretroviral treatment (HAART) in HIV-1 disease may vary between nucleoside-naive and experienced patients as well as between patients with different viral phenotypes and in different stages of disease. OBJECTIVE: To investigate variables of importance for successful long-term viral suppression by analysing virological, clinical and immunological characteristics at initiation of protease inhibitor treatment on suppression of HIV RNA over 1 year. DESIGN: An open, non-randomized, observational clinical study. SETTING: Venh?lsan, Department of Dermatovenereology, S?der Hospital, Stockholm, Sweden. PATIENTS: A total of 147 unselected advanced patients with known HIV-1 infection for a mean of 7 years, of whom 37% had AIDS and who started treatment with a protease inhibitor during 1996. INTERVENTIONS: All patients received HAART with at least two nucleoside analogues in combination with either indinavir (81%) or ritonavir (19%). The majority (77%) had been previously treated with nucleoside analogues for a mean of 39 months. MEASUREMENTS: CD4+ lymphocyte count, plasma HIV-1 RNA, viral phenotype and HIV-1 coreceptor CCR-5 genotype at baseline. Viral load and CD4+ lymphocyte count were determined every 3 months. RESULTS: Patients were analysed on an intention-to-treat basis. The mean CD4+ lymphocyte count at baseline was 170 x 10(6)/l and the median viral load was 68 600 copies/ml. Heterozygosity for the delta32 deletion of the CCR-5 gene (delta32/wt) was found in 27%. MT-2 positive virus (syncytium-inducing) was isolated in 46%. Logistic regression revealed that nucleoside analogue experience and baseline log10 HIV-1 RNA were the only factors independently related to plasma HIV-1 RNA levels below 500 copies/ml after 1 year of treatment, which was found in 69%. CONCLUSION: The virological outcome after 1 year of HAART was strongly correlated to prior treatment history and baseline viral load, whereas CD4+ lymphocyte count, CCR-5 genotype and viral biological phenotype had less influence. The long-term antiviral efficacy of HAART was lowest in individuals with previous nucleoside analogue treatment and a high baseline viral load. In these individuals an even more aggressive treatment should be considered.     

Maternal and viral factors in vertical transmission of HIV-1 subtype E

Lipids in the synovial fluid of patients with active rheumatoid arthritis are elevated compared to normal synovial fluid and that of other inflammatory arthropathies. Various assumptions about the role of these lipids have been made. This study offers evidence that these lipids may contribute to the synovitis in rheumatoid arthritis through participation in the arachidonic pathway within the joint space. Phospholipase A2 activity, phospholipids, prostaglandin E2, and leukotriene B4 have been correlated in the synovial fluid and plasma of untreated rheumatoid patients and compared with that of patients with osteoarthritis.     

The ability of HIV type 1 to use CCR-3 as a coreceptor is controlled by envelope V1/V2 sequences acting in conjunction with a CCR-5 tropic V3 loop

Although infection by primary HIV type 1 (HIV-1) isolates normally requires the functional interaction of the viral envelope protein with both CD4 and the CCR-5 coreceptor, a subset of such isolates also are able to use the distinct CCR-3 receptor. By analyzing the ability of a series of wild-type and chimeric HIV-1 envelope proteins to mediate CCR-3-dependent infection, we have determined that CCR-3 tropism maps to the V1 and V2 variable region of envelope. Although substitution of the V1/V2 region of a CCR-3 tropic envelope into the context of a CCR-5 tropic envelope is both necessary and sufficient to confer CCR-3 tropism, this same substitution has no phenotypic effect when inserted into a CXCR-4 tropic HIV-1 envelope context. However, this latter chimera acquires both CCR-3 and CCR-5 tropism when a CCR-5 tropic V3 loop sequence also is introduced. These data demonstrate that the V1/2 region of envelope can, like the V3 loop region, encode a particular coreceptor requirement and suggest that a functional envelope:CCR-3 interaction may depend on the cooperative interaction of CCR-3 with both the V1/V2 and the V3 region of envelope.