Chasing the infecting HIV-1.

In the absence of an effective prophylactic vaccine and successful viral eradication strategies, the burden of human immunodeficiency virus type 1 (HIV-1) infection and disease continues to grow worldwide. The events characterizing primary HIV-1 infection and the early stages of the infection have been the focus of extensive research addressing the modalities of HIV-1 transmission. A thorough understanding of the early viral and host interactions leading to the establishment of productive infection will provide the necessary evidence base for developing successful prophylactic and therapeutic tools, including drug regimens, vaccines, and microbicides, and for guiding clinical management and the optimal time for the initiation of antiretroviral therapy. From a global perspective, among the various possible modes of acquisition, the majority of new HIV-1 infections occur through sexual transmission across mucosal barriers. Early after infection, HIV-1 strains appear to be genetically homogenous but rapidly diversify into a swarm of related but genetically divergent variants that compose the viral quasispecies. The highest degree of diversification is observed in the envelope glycoprotein 120 (gp120), the target of strong immune responses, including T-cell–mediated and neutralizing antibodies [1, 2]. There is substantial evidence to indicate that the diverse quasispecies replicating in chronically infected individuals is forced through a genetic ‘‘bottleneck’’ at the time of transmission. As a result, the majority of transmission events leading to productive infection appear to be associated with 1 homogeneous founder virus, whereas transmission of multiple divergent species is regarded as much less frequent. One possible explanation is that transmissible HIV-1 strains show certain unique characteristics that allow them to overcome host defenses. The mechanisms by which this selective process leads to the transmission of a homogenous founder virus, and the role of virus and host determinants, however, remain largely unknown. To gain entry into target cells, HIV-1 envelope glycoproteins must interact with the CD4 receptor and 1 of several possible coreceptors on the host cell membrane. The most common coreceptors used by HIV-1 are CCR5 and CXCR4. Viral strains using either of the 2 coreceptors or both are referred to as R5, X4, and dually tropic viruses, respectively. Most of the viral determinants of coreceptor use appear to be located within the hypervariable region V3 of gp120. One interesting feature of the early phases of HIV-1 infection is the predominance of R5 viruses within the replicating quasispecies detected in plasma. It is when disease progression and profound immune compromise occur that CXCR4using variants start to emerge. Again, the events leading to the predominance of CCR5-using strains in the initial phases of HIV-1 infection remain incompletely understood, and both virusand hostrelated factors are speculated to play a role [3]. Various rates of viral diversity early after infection have been previously described according to the mode of transmission and type of viral clade, both of which are considered to be important influencing factors. Viral diversity is, however, not limited to certain modes of transmission or types of clades [4]. In heterosexual cohorts, heterogeneous variants have been described after transmission with different HIV-1 clades in 10%–24% of participants. Data on men who have sex with men (MSM) report a higher rate of diversity, up to 36% in a study by Li et al [5]. In the case of injection drug users (IDUs), Bar et al have described multivariant transmission in 60% of participants, which is a higher proportion than that observed after sexual transmission, suggesting that mucosal Received 17 August 2011; accepted 26 August 2011; electronically published 12 October 2011. Correspondence: Sabine Kinloch-de Loes, MD, Department of Infection and Immunity, Royal Free Campus, University College London, Rowland Hill St, London NW3 2PF, United Kingdom ([email protected]). Clinical Infectious Diseases 2011;53(12):1280–2 The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. 1058-4838/2011/5312-0017$14.00 DOI: 10.1093/cid/cir737