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The Bowman-Birk inhibitor (BBI), a soybean-derived protease inhibitor, is known to have anti-inflammatory effect in both in vitro and in vivo systems. Macrophages play a key role in inflammation and immune activation, which is implicated in HIV disease progression. Here, we investigated the effect of BBI on HIV infection of peripheral blood monocyte-derived macrophages. We demonstrated that BBI could potently inhibit HIV replication in macrophages without cytotoxicity. Investigation of the mechanism(s) of BBI action on HIV showed that BBI induced the expression of IFN-β and multiple IFN stimulated genes (ISGs), including Myxovirus resistance protein 2 (Mx2), 2',5'-oligoadenylate synthetase (OAS-1), Virus inhibitory protein (viperin), ISG15 and ISG56. BBI treatment of macrophages also increased the expression of several known HIV restriction factors, including APOBEC3F, APOBEC3G and tetherin. Furthermore, BBI enhanced the phosphorylation of IRF3, a key regulator of IFN-β. The inhibition of IFN-β pathway by the neutralization antibody to type I IFN receptor (Anti-IFNAR) abolished BBI-mediated induction of the anti-HIV factors and inhibition of HIV in macrophages. These findings that BBI could activate IFN-β-mediated signaling pathway, initialize the intracellular innate immunity in macrophages and potently inhibit HIV at multiple steps of viral replication cycle indicate the necessity to further investigate BBI as an alternative and cost-effective anti-HIV natural product.

Genome editing via CRISPR/Cas9 has become an efficient and reliable way to make precise, targeted changes to the genome of living cells. CXCR4 is a co-receptor for the human immunodeficiency virus type 1 (HIV-1) infection and has been considered as an important therapeutic target for AIDS. CXCR4 mediates viral entry into human CD4(+) cells by binding to envelope protein, gp120. Here, we show that human CXCR4 gene is efficiently disrupted by CRISPR/Cas9-mediated genome editing, leading to HIV-1 resistance of human primary CD4(+) T cells. We also show that the Cas9-mediated ablation of CXCR4 demonstrated high specificity and negligible off-target effects without affecting cell division and propagation. The precise and efficient genome editing of CXCR4 will provide a new strategy for therapeutic application against HIV-1 infection.

Background: Mucosally transmissible and pathogenic CCR5 (R5)-tropic simian-human immunodeficiency virus (SHIV) molecular clones are useful reagents to identity neutralization escape in HIV-1 vaccine experiments and to study the envelope evolutionary process and mechanistic basis for coreceptor switch during the course of natural infection., Results: We observed progression to AIDS in rhesus macaques infected intrarectally with molecular clones of the pathogenic R5 SHIVSF162P3N isolate. Expansion to CXCR4 usage was documented in one diseased macaque that mounted a neutralizing antibody response and in another that failed to do so, with the latter displaying a rapid progressor phenotype. V3 loop envelop glycoprotein gp120 sequence changes that are predictive of a CXCR4 (X4)-using phenotype in HIV-1 subtype B primary isolates, specifically basic amino acid substations at positions 11 (S11R), 24 (G24R) and 25 (D25K) of the loop were detected in the two infected macaques. Functional assays showed that envelopes with V3 S11R or D25K mutation were dual-tropic, infecting CD4+ target cells that expressed either the CCR5 or CXCR4 coreceptor. And, consistent with findings of coreceptor switching in macaques infected with the pathogenic isolate, CXCR4-using variant was first detected in the lymph node of the chronically infected rhesus monkey several weeks prior to its presence in peripheral blood. Moreover, X4 emergence in this macaque coincided with persistent peripheral CD4+ T cell loss and a decline in neutralizing antibody titer that are suggestive of immune deterioration, with macrophages as the major virus-producing cells at the end-stage of disease., Conclusions: The data showed that molecular clones derived from the R5 SHIVSF162P3N isolate are mucosally transmissible and induced disease in a manner similar to that observed in HIV-1 infected individuals, providing a relevant and useful animal infection model for in-depth analyses of host selection pressures and the env evolutionary changes that influence disease outcome, coreceptor switching and vaccine escape.

The increasing prevalence of HIV-1 subtype B' in China and Southeast Asia calls for efforts to develop a relevant animal model to study viral transmission and pathogenesis. Because there are significant differences between subtype B' HIV-1 and other chimeric simian/human immunodeficiency viru (SHIVs) in the env gene, a novel SHIV, designated SHIV(B'WHU), was generated by replacing counterparts of SHIV(SF33) with tat/rev/vpu/env genes derived from a primary, CCR5-tropic, subtype B' HIV-1 strain of a Chinese patient. SHIV(B'WHU) was able to replicate in rhesus peripheral blood mononuclear cells and used CCR5 as its major coreceptor. Moreover, after serial passages in Chinese macaques, the in vivo infectivity of SHIV(B'WHU) was enhanced, yet no significant sequence changes were found in viral envelopes, and the virus did not change its CCR5-tropism. CD4(+) T-cell loss, however, was found in the intraepithelial lymphocytes of small intestines of infected macaques. Our findings have implications in understanding the early pathogenesis of SHIV(B'WHU) in Chinese macaques.

We investigated transmission of human immunodeficiency virus type 1 (HIV-1) via breast-feeding by 104 Chinese mothers who acquired the infection through blood transfusion postnatally. Of 106 children, 38 (35.8%) were infected. All children survived to age 5 years, and their survival curve was similar to that of their mothers. These findings suggest a high rate of HIV-1 transmission via breast-feeding when mothers were infected postnatally via blood transfusion, perhaps because of the higher viremia expected during the acute phase of infection. The course of disease among infected children was significantly less rapid than that among newborns infected perinatally, suggesting that a brief window of HIV-1-free life often enables the immune system of an infant to stave off rapid disease progression.

Objective: To determine the prevalence of drug-resistant HIV-1 and the efficacy of first-line highly active antiretroviral therapy (HAART) regimens consisted of generic nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor among 339 study subjects in rural areas of Hubei province, China., Methods: Two cross-sectional studies were conducted to investigate 150 HAART-naive (99 received subsequent therapy) between 2003 and 2005 and 288 HAART-experienced patients mainly between 2005 and 2006. Patients' CD4+ T-cell count and viral load were determined. HIV-1 pol gene fragments were amplified from patients' plasma by reverse transcriptase-polymerase chain reaction, subsequently sequenced and analyzed., Results: About 83.5% of the patients were from rural villages. They were dominantly infected with subtype B' HIV-1 (96.7%) through paid blood donation (64.6%) and related blood transfusion (28.3%). We found that there was a steady increase of CD4 count over time among treated patients without detectable viral load (186/288, 64.6%). There was, however, an increasing prevalence of nucleoside reverse transcriptase inhibitor- and nonnucleoside reverse transcriptase inhibitor-resistant mutations among patients with detected viremia (102/288, 35.4%) after treatment for 3-6 (24.3%), 9-12 (57.1%), and 20-24 (63.3%) months, respectively. The increasing rates were associated with significant CD4 count drop and viral load increase. Some patients also developed multidrug-resistant mutants., Conclusions: : We report the first HIV-1 drug resistance study after 2 years on HAART among Chinese patients living in rural villages. Our data suggest that a significant portion of patients are failing first-line regimens with a trend of AIDS progression. It is therefore necessary to maximize the drug adherence and to make affordable second-line HAART regimens available immediately. Our results have implications for implementing HAART in underresourced developing country settings.