The CD4 binding site(CD4bs) of envelope glycoprotein(Env) is an important conserved target for anti-human immunodeficiency virus type 1(HIV-1) neutralizing antibodies. Neutralizing monoclonal antibodies IgG1 b12(b12) ...The CD4 binding site(CD4bs) of envelope glycoprotein(Env) is an important conserved target for anti-human immunodeficiency virus type 1(HIV-1) neutralizing antibodies. Neutralizing monoclonal antibodies IgG1 b12(b12) could recognize conformational epitopes that overlap the CD4 bs of Env. Different virus strains, even derived from the same individual, showed distinct neutralization susceptibility to b12. We examined the key amino acid residues affecting b12 neutralization susceptibility using single genome amplification and pseudovirus neutralization assay. Eleven amino acid residues were identified that affect the sensitivity of Env to b12. Through site-directed mutagenesis, an amino acid substitution at position 182 in the V2 region of Env was confirmed to play a key role in regulating the b12 neutralization susceptibility. The introduction of V182 L to a resistant strain enhanced its sensitivity to b12 more than twofold. Correspondingly, the introduction of L182 V to a sensitive strain reduced its sensitivity to b12 more than tenfold. Amino acid substitution at positions 267 and 346 could both enhance the sensitivity to b12 more than twofold. However, no additive effect was observed when the three site mutageneses were introduced into the same strain, and the sensitivity was equivalent to the single V182 L mutation. CRF07_BC is a major circulating recombinant form of HIV-1 prevalent in China. Our data may provide important information for understanding the molecular mechanism regulating the neutralization susceptibility of CRF07_BC viruses to b12 and may be helpful for a vaccine design targeting the CD4 bs epitopes.展开更多
The human immunodeficiency virus （HIV） lentiviral vector is an ideal vector for gene therapy. In the present study, the wild-type HIV-1 genome was segregated into four plasmids, and an optimized novel HIV-1 lentivir...The human immunodeficiency virus （HIV） lentiviral vector is an ideal vector for gene therapy. In the present study, the wild-type HIV-1 genome was segregated into four plasmids, and an optimized novel HIV-1 lentiviral vector containing green fluorescent protein and vesicular stomatitis virus G pseudo-capsule was constructed. The plasmids were pHR-CMV-EGFP, pCMVΔ8.9, pRSV-Rev, pCMV-VSV-G. The four plasmid system was co-transfected into 293T cells, and green fluorescent protein expression was observed. The present study obtained lentiviral particles by high-speed centrifugation, and the lentiviral particle titer was 4 × 108 TU/mL after centrifugation. Thus, an optimized novel HIV-1 lentiviral vector was successfully constructed.展开更多
In order to clarify the mechanism of inhibition of human neutrophil peptide-1 （HNP-1） on human immunodeficiency virus type 1（HIV-1）, CD4+ cells were used as the target cells for acute infection with HIV-1, and exp...In order to clarify the mechanism of inhibition of human neutrophil peptide-1 （HNP-1） on human immunodeficiency virus type 1（HIV-1）, CD4+ cells were used as the target cells for acute infection with HIV-1, and experiments were performed separately with the interaction of different concentrations of HNP-1 with free virus particles, un-infected and infected CD4+ cells. The activity of reverse transcriptase （RT） in the supernatant of cell cultures of different lots of experiments were then assayed accordingly, and the toxicity effect on human lymphocytic cells MT4 was measured by MTT assay. The experimental results showed that pre-incubation of HNP-1 with the concentrated stock of virus could block the binding of virus to target cells with EC50 of 2.49 μg/ml, while pre-treatment of CD4+ cells with HNP-1 prior to inoculation could reduce the ability of cells to bind virus with EC50 of 20.7 μg/ml. In addition, When culturing the infected CD4+ cells in the continuous presence of various concentrations of HNP-1 added immediately after infection, HNP-1 exhibited modest inhibitory effect on viral replication with reduced RT activities in comparison with those of the control group （P<0.05 at 100 μg/ml of the highest concentration）. No cytotoxicity effect of HNP-1 was observed as demonstrated by MTT assay. These results indicate that HNP-1 exerts anti-HIV activity by at least two levels: direct inactivation of virus particles and effect on the ability of target cells to bind with viruses. The evaluation of two parameters, inhibitory effect and the cytotoxicity renders HNP-1 an available candidate for anti-HIV therapeutic agent.展开更多
Due to significant advances in the treatment of human immunodeficiency virus type-1(HIV-1), HIV-1 infection gradually has become a treatable chronic disease. Successfully treated HIV-positive individuals can have a no...Due to significant advances in the treatment of human immunodeficiency virus type-1(HIV-1), HIV-1 infection gradually has become a treatable chronic disease. Successfully treated HIV-positive individuals can have a normal life expectancy. Hence, more and more HIV-1 discordant couples in Taiwan and the rest of the world are seeking fertility assistance. Pre-treatment of highly active antiretroviral therapy(HAART) combined with sperm washing and RT-polymerase chain reaction examination for HIV-1 viral load has become the standard procedure to assist them to conceive. However,in order to reduce the transmission risk to the lowest level for the couple and to diminish the cost of health care for the insurance institutes or government, in vitro fertilization(IVF)-intracytoplasmic sperm injection(ICSI) therapy provides the ideal solution for HIV-1 discordant couples with infected men. Intrauterine insemination(IUI) theoretically introduces more than 107 times of sperm counts or semen volume to uninfected women vs IVF-ICSI. However, since some regimens of HAART may significantly decrease the sperm motility, compared to IVF-ICSI, IUI only produces 1/5 to 1/2 pregnancy rates per cycle. Given the risk of seroconversion of HIV infection which actually happens after successful treatment, IVF-ICSI for these HIV-1 seropositive men is more cost-effective and should be the first line treatment for these cases.展开更多
Human T-cell lymphotropic virus type 1(HTLV-1)-associated myelopathy/tropical spastic paraparesis(HAM/TSP) is a slowly progressive neurodegenerative disorder in which lesions of the central nervous system cause progre...Human T-cell lymphotropic virus type 1(HTLV-1)-associated myelopathy/tropical spastic paraparesis(HAM/TSP) is a slowly progressive neurodegenerative disorder in which lesions of the central nervous system cause progressive weakness, stiffness, and a lower limb spastic paraparesis. In some cases, polymyositis, inclusion bodymyositis, or amyotrophic lateral sclerosis-like syndromes are associated with HTLV-1. TSP was first described in Jamaica in 1888 and known as Jamaican peripheral neuritis before TSP was related to HTLV-1 virus, the first retrovirus being identified, and the disease is since named HAM/TSP. There is no established treatment program for HAM/TSP. Prevention is difficult in lowincome patients(i.e., HTLV-1 infected breast feeding mothers in rural areas, sex workers). Thus, there is a need for new therapeutic avenues. Therapeutic approaches must be based on a better understanding, not only of clinical and clinicopathological data, but also of the pathophysiology of the affection. Consequently, a better understanding of existing or newly developed animal models of HAM/TSP is a prerequisite step in the development of new treatments.展开更多
Objective： To explore the functions and mechanisms of herpes simplex virus type I（HSV-1） while infecting human oral epithelial cells in vitro（being similar to the infection in vivo）. Methods：An abundance of HSV-...Objective： To explore the functions and mechanisms of herpes simplex virus type I（HSV-1） while infecting human oral epithelial cells in vitro（being similar to the infection in vivo）. Methods：An abundance of HSV-1 strains amplified in Vero cells were used to infect human oral epithelial cells. The culture supernatant was collected to infect Vero cells again. Morphology of HSV-1 was identified by inverted microscope and transmission electron microscope. Nucleic acid of the virus was detected by PCR. Results：The infected human oral epithelial cells didn＇ t display an obvious cytopathic effect（CPE） under inverted microscope（while Vero cells which were infected by the culture supernatant showed typical（CPE）. The virus particles were not observed in the cytoplasm nor in nucleus of human oral epithelial cells, however under transmission electron microscope in the cytoplasm of Vero cells, the nucleic acid of HSV-1 could be detected in infected human oral epithelial cells, by PCR. Conclusion-HSV-1 can successfully infect human oral epithelial cells. This model may provide a useful approach for studying the pathogenesis of herpes virus-associated periodontal disease.展开更多
AIM:To corroborate the capacity of Phyto V7,a complex of phytochemicals,to improve the physical well-being of human immunodeficiency virus-1(HIV-1) infected and acquired immune deficiency syndrome(AIDS) patients not u...AIM:To corroborate the capacity of Phyto V7,a complex of phytochemicals,to improve the physical well-being of human immunodeficiency virus-1(HIV-1) infected and acquired immune deficiency syndrome(AIDS) patients not undergoing antiretroviral treatment.METHODS:Two hundred and thirty nine HIV-1 seropositive male and female voluntary inmates were recruited through the Uruguay National Program of AIDS.The study participants received for 90 consecutive days every eight hours two tablets(760 mg/each) of Phyto V7,containing a mix of the following phytochemicals:flavonols(Kaempferol,Quercetin),flavones(Apigenin,Luteolin),hydroxycinnamic acids(ferrulic acid),carotenoids(Lutein,Lycopene,Beta carotene) and organosulfur compounds,all from vegetal origin.The participants did not receive any antiretroviral treatment during the study.At days 0,30,60 and 90(± 2 d) the participants were evaluated for body mass index(BMI),tolerance to Phyto V7 and Index of Quality of Life based on the Karfnosky scale.ANOVA,Tukey Post-test,χ2 test and Wilcoxon Signed Rank test were used to analyze the effect of treatment.RESULTS:One hundred and nighty nine study participants finished the study.Already after 30 d of Phyto V7 consumption,the weight,BMI and Karnofsky score statistically significantly improved(P < 0.001),and continued to improve until the end of the study.The mean weight gain per participant during the 90 d wasof 1.21 kg(approximately 2% of body weight).The overall increase in the mean Karnofsky score after 90 d was 14.08%.The lower the BMI and Karnofsky score of the participants were at the beginning of the study,the more notorious was the improvement over time.For example,the mean increment of Index of Quality of Life,among the participants with an initial Karnofsky score of 5 or below(n = 33) from day 0 to day 90,was of 35.67%(0.476 ± 0.044 vs 0.645 ± 0.09; P < 0.001).The tolerability to Phyto V7 was very good and no adverse reactions were recorded or reported.CONCLUSION:Administration of the Phyto V7 can be an important tool to improve the well-being of HIV-1 seropositive individuals and AIDS patients,not undergoing antiretroviral treatment.展开更多
Human T lymphotropic virus type 1 (HTLV-1) is endemic in the southern part of Japan. Infection of the virus can cause adult T cell leukemia/lymphoma (ATL), while most infected individuals remain in a carrier state for...Human T lymphotropic virus type 1 (HTLV-1) is endemic in the southern part of Japan. Infection of the virus can cause adult T cell leukemia/lymphoma (ATL), while most infected individuals remain in a carrier state for a long period of time. Although rare cases of carriers, like ATL patients, who developed opportunistic infections, have been reported, hematological changes of carriers who are prone to opportunistic infections have not been well defined. Here, we present a case of an HTLV-1 carrier who developed Mycobacterium intracellulare infection and Pneumocystis jirovecii pneumonia (PcP) simultaneously. Flow cytometric analysis of bone marrow cells revealed an aberrant compositional change similar to that in ATL patients. This suggests the presence of a pre-ATL state prior to the development of ATL, which is notable in terms of underlying cellular immunodeficiency.展开更多
Human immunodeficiency virus type 1(HIV-1) persistence is a major barrier to the successful treatment and eradication of acquired immunodeficiency syndrome(AIDS).In addition to resting CD4+ T cells,a significant long-...Human immunodeficiency virus type 1(HIV-1) persistence is a major barrier to the successful treatment and eradication of acquired immunodeficiency syndrome(AIDS).In addition to resting CD4+ T cells,a significant long-lived compartment of HIV-1 infection in vivo includes blood monocytes and tissue macrophages.Studying HIV-1 persistence in monocyte-lineage cells is critical because these cells are important HIV-1 target cells in vivo.Monocyte-lineage cells,including monocytes,dendritic cells(DCs) and macrophages,play a significant role in HIV-1 infection and transmission.These cells have been implicated as viral reservoirs that facilitate HIV-1 latency and persistence.A better understanding of HIV-1 interactions with monocyte-lineage cells can potentially aid in the development of new approaches for intervention.This minireview highlights the latest advances in understanding the role of monocyte-lineage cells in HIV-1 persistence and emphasizes new insights into the mechanisms underlying viral persistence.展开更多
While human immunodeficiency virus 1(HIV-1) infectionis controlled through continuous, life-long use of a combination of drugs targeting different steps of the virus cycle, HIV-1 is never completely eradicated from th...While human immunodeficiency virus 1(HIV-1) infectionis controlled through continuous, life-long use of a combination of drugs targeting different steps of the virus cycle, HIV-1 is never completely eradicated from the body. Despite decades of research there is still no effective vaccine to prevent HIV-1 infection. Therefore, the possibility of an RNA interference(RNAi)-based cure has become an increasingly explored approach. Endogenous gene expression is controlled at both, transcriptional and post-transcriptional levels by noncoding RNAs, which act through diverse molecular mechanisms including RNAi. RNAi has the potential to control the turning on/off of specific genes through transcriptional gene silencing(TGS), as well as finetuning their expression through post-transcriptional gene silencing(PTGS). In this review we will describe in detail the canonical RNAi pathways for PTGS and TGS, the relationship of TGS with other silencing mechanisms and will discuss a variety of approaches developed to suppress HIV-1 via manipulation of RNAi. We will briefly compare RNAi strategies against other approaches developed to target the virus, highlighting their potential to overcome the major obstacle to finding a cure, which is the specific targeting of the HIV-1 reservoir within latently infected cells.展开更多
HIV-1 evolves strongly and undergoes geographic differentiation as it spreads in diverse host populations around the world.For instance,distinct genomic backgrounds can be observed between the pandemic subtype B,preva...HIV-1 evolves strongly and undergoes geographic differentiation as it spreads in diverse host populations around the world.For instance,distinct genomic backgrounds can be observed between the pandemic subtype B,prevalent in Europe and North-America,and its offspring clade B' in East Asia.Here we ask whether this differentiation affects the selection pressure experienced by the virus.To answer this question we evaluate selection pressure on the HIV-1 envelope protein gp120at the level of individual codons using a simple and fast estimation method based on the ratio k_alk_s of amino acid changes to synonymous changes.To validate the approach we compare results to those from a state-of-the-art mixed-effect method.The agreement is acceptable,but the analysis also demonstrates some limitations of the simpler approach.Further,we find similar distributions of codons under stabilizing and directional selection pressure in gp120 for subtypes B and B' with more directional selection pressure in variable loops and more stabilizing selection in the constant regions.Focusing on codons with increased k_alk_s values in B',we show that these codons are scattered over the whole of gp120,with remarkable clusters of higher density in regions flanking the variable loops.We identify a significant statistical association of glycosylation sites and codons with increased k_alk_s values.展开更多
基金supported by grants from National Science and Technology Major Project(2012ZX10004701)
文摘The CD4 binding site(CD4bs) of envelope glycoprotein(Env) is an important conserved target for anti-human immunodeficiency virus type 1(HIV-1) neutralizing antibodies. Neutralizing monoclonal antibodies IgG1 b12(b12) could recognize conformational epitopes that overlap the CD4 bs of Env. Different virus strains, even derived from the same individual, showed distinct neutralization susceptibility to b12. We examined the key amino acid residues affecting b12 neutralization susceptibility using single genome amplification and pseudovirus neutralization assay. Eleven amino acid residues were identified that affect the sensitivity of Env to b12. Through site-directed mutagenesis, an amino acid substitution at position 182 in the V2 region of Env was confirmed to play a key role in regulating the b12 neutralization susceptibility. The introduction of V182 L to a resistant strain enhanced its sensitivity to b12 more than twofold. Correspondingly, the introduction of L182 V to a sensitive strain reduced its sensitivity to b12 more than tenfold. Amino acid substitution at positions 267 and 346 could both enhance the sensitivity to b12 more than twofold. However, no additive effect was observed when the three site mutageneses were introduced into the same strain, and the sensitivity was equivalent to the single V182 L mutation. CRF07_BC is a major circulating recombinant form of HIV-1 prevalent in China. Our data may provide important information for understanding the molecular mechanism regulating the neutralization susceptibility of CRF07_BC viruses to b12 and may be helpful for a vaccine design targeting the CD4 bs epitopes.
基金the National Natural Science Foundation of China, No. 30770755
文摘The human immunodeficiency virus （HIV） lentiviral vector is an ideal vector for gene therapy. In the present study, the wild-type HIV-1 genome was segregated into four plasmids, and an optimized novel HIV-1 lentiviral vector containing green fluorescent protein and vesicular stomatitis virus G pseudo-capsule was constructed. The plasmids were pHR-CMV-EGFP, pCMVΔ8.9, pRSV-Rev, pCMV-VSV-G. The four plasmid system was co-transfected into 293T cells, and green fluorescent protein expression was observed. The present study obtained lentiviral particles by high-speed centrifugation, and the lentiviral particle titer was 4 × 108 TU/mL after centrifugation. Thus, an optimized novel HIV-1 lentiviral vector was successfully constructed.
文摘In order to clarify the mechanism of inhibition of human neutrophil peptide-1 （HNP-1） on human immunodeficiency virus type 1（HIV-1）, CD4+ cells were used as the target cells for acute infection with HIV-1, and experiments were performed separately with the interaction of different concentrations of HNP-1 with free virus particles, un-infected and infected CD4+ cells. The activity of reverse transcriptase （RT） in the supernatant of cell cultures of different lots of experiments were then assayed accordingly, and the toxicity effect on human lymphocytic cells MT4 was measured by MTT assay. The experimental results showed that pre-incubation of HNP-1 with the concentrated stock of virus could block the binding of virus to target cells with EC50 of 2.49 μg/ml, while pre-treatment of CD4+ cells with HNP-1 prior to inoculation could reduce the ability of cells to bind virus with EC50 of 20.7 μg/ml. In addition, When culturing the infected CD4+ cells in the continuous presence of various concentrations of HNP-1 added immediately after infection, HNP-1 exhibited modest inhibitory effect on viral replication with reduced RT activities in comparison with those of the control group （P<0.05 at 100 μg/ml of the highest concentration）. No cytotoxicity effect of HNP-1 was observed as demonstrated by MTT assay. These results indicate that HNP-1 exerts anti-HIV activity by at least two levels: direct inactivation of virus particles and effect on the ability of target cells to bind with viruses. The evaluation of two parameters, inhibitory effect and the cytotoxicity renders HNP-1 an available candidate for anti-HIV therapeutic agent.
文摘Due to significant advances in the treatment of human immunodeficiency virus type-1(HIV-1), HIV-1 infection gradually has become a treatable chronic disease. Successfully treated HIV-positive individuals can have a normal life expectancy. Hence, more and more HIV-1 discordant couples in Taiwan and the rest of the world are seeking fertility assistance. Pre-treatment of highly active antiretroviral therapy(HAART) combined with sperm washing and RT-polymerase chain reaction examination for HIV-1 viral load has become the standard procedure to assist them to conceive. However,in order to reduce the transmission risk to the lowest level for the couple and to diminish the cost of health care for the insurance institutes or government, in vitro fertilization(IVF)-intracytoplasmic sperm injection(ICSI) therapy provides the ideal solution for HIV-1 discordant couples with infected men. Intrauterine insemination(IUI) theoretically introduces more than 107 times of sperm counts or semen volume to uninfected women vs IVF-ICSI. However, since some regimens of HAART may significantly decrease the sperm motility, compared to IVF-ICSI, IUI only produces 1/5 to 1/2 pregnancy rates per cycle. Given the risk of seroconversion of HIV infection which actually happens after successful treatment, IVF-ICSI for these HIV-1 seropositive men is more cost-effective and should be the first line treatment for these cases.
文摘Human T-cell lymphotropic virus type 1(HTLV-1)-associated myelopathy/tropical spastic paraparesis(HAM/TSP) is a slowly progressive neurodegenerative disorder in which lesions of the central nervous system cause progressive weakness, stiffness, and a lower limb spastic paraparesis. In some cases, polymyositis, inclusion bodymyositis, or amyotrophic lateral sclerosis-like syndromes are associated with HTLV-1. TSP was first described in Jamaica in 1888 and known as Jamaican peripheral neuritis before TSP was related to HTLV-1 virus, the first retrovirus being identified, and the disease is since named HAM/TSP. There is no established treatment program for HAM/TSP. Prevention is difficult in lowincome patients(i.e., HTLV-1 infected breast feeding mothers in rural areas, sex workers). Thus, there is a need for new therapeutic avenues. Therapeutic approaches must be based on a better understanding, not only of clinical and clinicopathological data, but also of the pathophysiology of the affection. Consequently, a better understanding of existing or newly developed animal models of HAM/TSP is a prerequisite step in the development of new treatments.
文摘Objective： To explore the functions and mechanisms of herpes simplex virus type I（HSV-1） while infecting human oral epithelial cells in vitro（being similar to the infection in vivo）. Methods：An abundance of HSV-1 strains amplified in Vero cells were used to infect human oral epithelial cells. The culture supernatant was collected to infect Vero cells again. Morphology of HSV-1 was identified by inverted microscope and transmission electron microscope. Nucleic acid of the virus was detected by PCR. Results：The infected human oral epithelial cells didn＇ t display an obvious cytopathic effect（CPE） under inverted microscope（while Vero cells which were infected by the culture supernatant showed typical（CPE）. The virus particles were not observed in the cytoplasm nor in nucleus of human oral epithelial cells, however under transmission electron microscope in the cytoplasm of Vero cells, the nucleic acid of HSV-1 could be detected in infected human oral epithelial cells, by PCR. Conclusion-HSV-1 can successfully infect human oral epithelial cells. This model may provide a useful approach for studying the pathogenesis of herpes virus-associated periodontal disease.
文摘AIM:To corroborate the capacity of Phyto V7,a complex of phytochemicals,to improve the physical well-being of human immunodeficiency virus-1(HIV-1) infected and acquired immune deficiency syndrome(AIDS) patients not undergoing antiretroviral treatment.METHODS:Two hundred and thirty nine HIV-1 seropositive male and female voluntary inmates were recruited through the Uruguay National Program of AIDS.The study participants received for 90 consecutive days every eight hours two tablets(760 mg/each) of Phyto V7,containing a mix of the following phytochemicals:flavonols(Kaempferol,Quercetin),flavones(Apigenin,Luteolin),hydroxycinnamic acids(ferrulic acid),carotenoids(Lutein,Lycopene,Beta carotene) and organosulfur compounds,all from vegetal origin.The participants did not receive any antiretroviral treatment during the study.At days 0,30,60 and 90(± 2 d) the participants were evaluated for body mass index(BMI),tolerance to Phyto V7 and Index of Quality of Life based on the Karfnosky scale.ANOVA,Tukey Post-test,χ2 test and Wilcoxon Signed Rank test were used to analyze the effect of treatment.RESULTS:One hundred and nighty nine study participants finished the study.Already after 30 d of Phyto V7 consumption,the weight,BMI and Karnofsky score statistically significantly improved(P < 0.001),and continued to improve until the end of the study.The mean weight gain per participant during the 90 d wasof 1.21 kg(approximately 2% of body weight).The overall increase in the mean Karnofsky score after 90 d was 14.08%.The lower the BMI and Karnofsky score of the participants were at the beginning of the study,the more notorious was the improvement over time.For example,the mean increment of Index of Quality of Life,among the participants with an initial Karnofsky score of 5 or below(n = 33) from day 0 to day 90,was of 35.67%(0.476 ± 0.044 vs 0.645 ± 0.09; P < 0.001).The tolerability to Phyto V7 was very good and no adverse reactions were recorded or reported.CONCLUSION:Administration of the Phyto V7 can be an important tool to improve the well-being of HIV-1 seropositive individuals and AIDS patients,not undergoing antiretroviral treatment.
文摘Human T lymphotropic virus type 1 (HTLV-1) is endemic in the southern part of Japan. Infection of the virus can cause adult T cell leukemia/lymphoma (ATL), while most infected individuals remain in a carrier state for a long period of time. Although rare cases of carriers, like ATL patients, who developed opportunistic infections, have been reported, hematological changes of carriers who are prone to opportunistic infections have not been well defined. Here, we present a case of an HTLV-1 carrier who developed Mycobacterium intracellulare infection and Pneumocystis jirovecii pneumonia (PcP) simultaneously. Flow cytometric analysis of bone marrow cells revealed an aberrant compositional change similar to that in ATL patients. This suggests the presence of a pre-ATL state prior to the development of ATL, which is notable in terms of underlying cellular immunodeficiency.
基金supported in part by grants(AI068493 and AI078762)from the National Institutes of Health,USA
文摘Human immunodeficiency virus type 1(HIV-1) persistence is a major barrier to the successful treatment and eradication of acquired immunodeficiency syndrome(AIDS).In addition to resting CD4+ T cells,a significant long-lived compartment of HIV-1 infection in vivo includes blood monocytes and tissue macrophages.Studying HIV-1 persistence in monocyte-lineage cells is critical because these cells are important HIV-1 target cells in vivo.Monocyte-lineage cells,including monocytes,dendritic cells(DCs) and macrophages,play a significant role in HIV-1 infection and transmission.These cells have been implicated as viral reservoirs that facilitate HIV-1 latency and persistence.A better understanding of HIV-1 interactions with monocyte-lineage cells can potentially aid in the development of new approaches for intervention.This minireview highlights the latest advances in understanding the role of monocyte-lineage cells in HIV-1 persistence and emphasizes new insights into the mechanisms underlying viral persistence.
文摘While human immunodeficiency virus 1(HIV-1) infectionis controlled through continuous, life-long use of a combination of drugs targeting different steps of the virus cycle, HIV-1 is never completely eradicated from the body. Despite decades of research there is still no effective vaccine to prevent HIV-1 infection. Therefore, the possibility of an RNA interference(RNAi)-based cure has become an increasingly explored approach. Endogenous gene expression is controlled at both, transcriptional and post-transcriptional levels by noncoding RNAs, which act through diverse molecular mechanisms including RNAi. RNAi has the potential to control the turning on/off of specific genes through transcriptional gene silencing(TGS), as well as finetuning their expression through post-transcriptional gene silencing(PTGS). In this review we will describe in detail the canonical RNAi pathways for PTGS and TGS, the relationship of TGS with other silencing mechanisms and will discuss a variety of approaches developed to suppress HIV-1 via manipulation of RNAi. We will briefly compare RNAi strategies against other approaches developed to target the virus, highlighting their potential to overcome the major obstacle to finding a cure, which is the specific targeting of the HIV-1 reservoir within latently infected cells.
基金Deutsche Forschungsgemeinschaft(http://www.dfg.de),grant TRR60/A6the University of Duisburg-Essen(http://www.uni-due.de)the Chinese Key National Science and Technology Program in the 12th Five-YearPeriod,grant 2012ZX10001006-002
文摘HIV-1 evolves strongly and undergoes geographic differentiation as it spreads in diverse host populations around the world.For instance,distinct genomic backgrounds can be observed between the pandemic subtype B,prevalent in Europe and North-America,and its offspring clade B' in East Asia.Here we ask whether this differentiation affects the selection pressure experienced by the virus.To answer this question we evaluate selection pressure on the HIV-1 envelope protein gp120at the level of individual codons using a simple and fast estimation method based on the ratio k_alk_s of amino acid changes to synonymous changes.To validate the approach we compare results to those from a state-of-the-art mixed-effect method.The agreement is acceptable,but the analysis also demonstrates some limitations of the simpler approach.Further,we find similar distributions of codons under stabilizing and directional selection pressure in gp120 for subtypes B and B' with more directional selection pressure in variable loops and more stabilizing selection in the constant regions.Focusing on codons with increased k_alk_s values in B',we show that these codons are scattered over the whole of gp120,with remarkable clusters of higher density in regions flanking the variable loops.We identify a significant statistical association of glycosylation sites and codons with increased k_alk_s values.
