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1. Virus coreceptor interactions in HIV pathogenesis

Lecture given at a Minisymposium, Lund University, May 9, 2005

HIV-1 uses, in addition to CD4, the chemokine receptors CCR5 and/or CXCR4, for entry into host cells. HIV-1 with CCR5 use (R5 phenotype) usually dominates the early stages of infection. As a rule, evolution of HIV-1 coreceptor use is described as the acquisition of CXCR4-using virus (X4 or R5X4 phenotype). Appearance of CXCR4-using virus (switch) is linked to accelerated disease progression. However, the change in receptor use occurs in only approximately one half of HIV-1 infected (switch virus patients). Others maintain virus with CCR5 use throughout the course of disease (nonswitch virus patients). Our studies have shown that evolution occurs within the R5 phenotype as well. By use of chimeric receptors between CCR5 and CXCR4, we showed that R5 evolution goes from exclusive use of CCR5 (R5narrow phenotype) to broad use of chimeric receptors (R5broad) during disease progression. However, this evolution appeared to be different in switch and nonswitch virus patients. Such that virus from nonswitch virus patients became resistant to inhibition by the CCR5 ligand RANTES, whereas the virus from switch virus patients remained sensitive to inhibition by RANTES. This could be explained by differential use of CCR5 by the two groups of viruses.

2. Understandig HIV neutralization: What can we learn from the SIV model?

Lecture held at the conference on HIV neutralizing antibodies: relevance to pathogenesis and vaccines Nobel Forum, Karolinska Institutet, Stockholm, Sweden, October 27, 2006

This lecture summarized our accumulated knowledge on neutralization of primate lentiviruses, simian and human immunodeficiency viruses type 1 and type 2 (SIV, HIV-1 and HIV-2, respectively). Neutralization escape was demonstrated in the pathogenic infection with SIV in the macaque and with HIV-1 in the human host, whereas escape could not be demonstrated in the low pathogenic HIV-2 infection of either host. Escape from neutralization by the antibodies of the host (autologous neutralization) occurred in a time-dependent and pathogenesis related manner, such that escape was faster in more severe infections. Broadly cross-reactive neutralization, that is the capacity of serum to neutralize a broad range of virus variants (also called heterologous neutralization), was likely associated with long-term non-progression (LTNP) in SIV-infected macaques as well as in HIV-1-infected human hosts.

The role of viral envelope conformation in escape from neutralizing antibodies has been explored by testing the extent of CD4-dependence of CCR5 receptor use at cell entry. Accordingly, an open envelope structure indicated by CD4-independent use of CCR5 would confer a neutralization sensitive phenotype. Comparison of the three types of viruses showed that the HIV-1 envelope had the most closed conformation and was the least flexible than either HIV-2 or SIV.

3. Early broad neutralizing antibodies in long-term control of simian immunodeficiency virus (SIV) infection

Lecture given at an Advanced Immunology Course: Immunology in the Tropics, Entebbe, Uganda, September 2010

In a longitudinal study of clinical and evolutionary responses to transient treatment in 12 experimentally infected macaques, subjects show clear stratification into two groups based on viral load, immunological response, and evolutionary factors. Subjects that controlled viremia following withdrawal of treatment developed broadly neutralizing antibody responses earlier than subjects with no or transient control of viremia. Moreover, this latter group of macaques with higher viral loads showed greater divergence of SIV sequences, greater numbers of positively-selected amino-acid substitutions and a stronger neutralizing antibody response. The increase in effective population size started at an early stage of infection. The authors propose that this early phase of evolution is principally responsible for the later failure to control viremia and resulted in the development of potent neutralizing capacity.