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Viruses 2012, 4, 309-324; doi:10.3390/v4020309 OPEN ACCESS viruses ISSN 1999-4915 /journal/viruses Review Novel Approaches to Inhibit HIV Entry Chukwuka A. Didigu and Robert W. Doms * Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, 3610 Hamilton Walk, Philadelphia, PA 19104, USA; E-Mail: cdidigu@ * Author to whom correspondence should be addressed; E-Mail: doms@; Tel.: +1-215-898-0890; Fax: +1-215-898-9557. Received: 16 December 2011; in revised form: 17 January 2012 / Accepted: 7 February 2012 / Published: 21 February 2012 Abstract: Human Immunodeficiency Virus (HIV) entry into target cells is a multi-step process involving binding of the viral glycoprotein, Env, to its receptor CD4 and a coreceptor—either CCR5 or CXCR4. Understanding the means by which HIV enters cells has led to the identification of genetic polymorphisms, such as the 32 base-pair deletion in the ccr5 gene (ccr5∆32) that confers resistance to infection in homozygous individuals, and has also resulted in the development of entry inhibitors—small molecule antagonists that block infection at the entry step. The recent demonstration of long-term control of HIV infection in a leukemic patient following a hematopoietic stem cell transplant using cells from a ccr5∆32 homozygous donor highlights the important role of the HIV entry in maintaining an established infection an