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1.
Sci Adv ; 5(9): eaav2045, 2019 09.
Article in English | MEDLINE | ID: mdl-31579817

ABSTRACT

HIV persistence during combination antiretroviral therapy (cART) is the principal obstacle to cure. Mechanisms responsible for persistence remain uncertain; infections may be maintained by persistence and clonal expansion of infected cells or by ongoing replication in anatomic locations with poor antiretroviral penetration. These mechanisms require different strategies for eradication, and determining their contributions to HIV persistence is essential. We used phylogenetic approaches to investigate, at the DNA level, HIV populations in blood, lymphoid, and other infected tissues obtained at colonoscopy or autopsy in individuals who were on cART for 8 to 16 years. We found no evidence of ongoing replication or compartmentalization of HIV; we did detect clonal expansion of infected cells that were present before cART. Long-term persistence, and not ongoing replication, is primarily responsible for maintaining HIV. HIV-infected cells present when cART is initiated represent the only identifiable source of persistence and is the appropriate focus for eradication.


Subject(s)
HIV Infections/virology , HIV/physiology , Virus Replication , Adolescent , Adult , Anti-HIV Agents/pharmacology , Anti-HIV Agents/therapeutic use , Antiretroviral Therapy, Highly Active , Child , Female , HIV/classification , HIV/drug effects , HIV/genetics , HIV Infections/drug therapy , Humans , Male , Organ Specificity , Phylogeny , RNA, Viral , Sequence Analysis, DNA , Virus Replication/drug effects , Young Adult
2.
J Infect Dis ; 193(8): 1172-7, 2006 Apr 15.
Article in English | MEDLINE | ID: mdl-16544259

ABSTRACT

Therapy for hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)-infected patients results in modest cure rates. Gene expression patterns in peripheral blood mononuclear cells from 29 patients coinfected with HIV and HCV were used to predict virological response to therapy for HCV infection. Prediction analysis using pretherapy samples identified 79 genes that correctly classified all 10 patients who did not respond to therapy, 8 of 10 patients with a response at the end of treatment, and 7 of 9 patients with sustained virological response (86% overall). Analysis of 17 posttreatment samples identified 105 genes that correctly classified all 9 patients with response at the end of treatment and 7 of 8 patients with sustained virological response (94% overall). Failure of anti-HCV therapy was associated with elevated expression of interferon-stimulated genes. Gene expression patterns may provide a tool to predict anti-HCV therapeutic response.


Subject(s)
Gene Expression Regulation, Viral/physiology , HIV Infections/complications , Hepatitis C/complications , Hepatitis C/drug therapy , Leukocytes, Mononuclear/physiology , Adult , Female , Gene Expression Profiling , Humans , Interferons/biosynthesis , Male , Middle Aged , Oligonucleotide Array Sequence Analysis/methods , Statistics as Topic , Treatment Outcome , Up-Regulation
3.
J Dermatol Sci ; 19(2): 78-88, 1999 Feb.
Article in English | MEDLINE | ID: mdl-10098699

ABSTRACT

In 1998 it is appropriate to commemorate the 50th anniversary of el Mofty's use of purified 8-methoxypsoralen (8-MOP) in the treatment of vitiligo (el Mofty AM. A preliminary clinical report on the treatment of leukoderma with Ammi majus linn. J R Egypt Med Assn 1948,31:651 65. el Mofty AM, el Sawalhy H, el Mofty M. Clinical study of a new preparation of 8-methoxypsoralen in photochemotherapy. Int J Dermatol 1994;8:588 92). Two young American dermatologists (Aaron Lerner and Thomas Fitzpatrick) were intrigued by the potency of this material. After Lerner determined that artificial long wavelength ultraviolet (320-400 nm, UVA) radiation was the most efficient for activating 8-MOP. the development of artificial sources enabled the efficient delivery of these photons to skin containing 8-MOP. Their initial studies for vitiligo led to further development of this therapy for the treatment of psoriasis (Parrish JA, Fitzpatrick TB, Tannenbaum L, et al. Photochemotherapy of psoriasis with oral methoxsalen and long-wave ultraviolet light. New Engl J Med 1974;291:1207-11. Honigsmann H, Fitzpatrick TB, Pathak MA, et al. Oral photochemotherapy with psoralen and UVA (PUVA): principles and practice. In: Fitzpatrick TB, Eisen AZ, Wolf K, editors. Dermatology in General Medicine. New York: McGraw-Hill, 1987:1728-54). This photochemotherapy came to be called 'PUVA' (psoralen + UVA). The position PUVA holds today as one of the most common procedures performed in dermatology can be traced to their initial curiosity and their subsequent ingenuity. Further developments in more recent years capitalized on their seminal work. The therapy met with unprecedented success from the outset, leaving little perceived need to understand underlying science. However, in recent years there has been a new found interest in the basic aspects of psoralen photobiology and molecular mechanistic events contributing to therapeutic responses as well as to the development of skin cancers in PUVA patients. These will be surveyed in this review commemorating the 50 years of modern psoralen photobiology and photomedicine.


Subject(s)
Methoxsalen/history , Photobiology/history , Photochemotherapy/history , Photosensitizing Agents/history , Animals , Forecasting , History, 20th Century , Humans , Photobiology/trends , Photochemotherapy/trends
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