Viral Immune Pathogenesis

The research group of Dr. Neeltje Kootstra (Head Laboratory of Viral Immune Pathogenesis) focuses mainly on virus-host interactions in HIV-1, HBV and HCV infection and pathogenesis.

We also participate in the Amsterdam Cohort studies, the AGEhIV cohort study and COBRA and as part of these studies, we maintain the biobanks and perform cohort-related research (Clinical monitoring).

    HIV-1 evolution

    HIV-1 has a high genetic variability and can vary with respect to biological properties such as coreceptor usage, cell tropism, and replication rate. The reverse transcriptase machinery of the virus creates mutations and mutant viruses may be selected if they have an advantage over coexisting virus variants that lack the mutation. For instance, in the presence of CTL, virus variants will be selected that accidentally have mutations in the CTL epitope, providing the virus with an escape mechanism.

    In the past, we have focused on the evolution of virus variants that differed with respect to co-receptor usage. Early in infection, HIV-1 variants that only use C-C chemokine receptor 5 (CCR5; R5 variants) predominate. With progression of disease, virus variants that use C-X-C receptor 4 (CXCR4; X4 variants) emerge in about 50% of individuals.

    Our current research focuses on the effect of the adaptive (e.g. CTL, antibodies) and innate immunity (e.g. restriction factors) on HIV-1 evolution and the effect of escape mutations on viral replication fitness.

    Host cell factors involved in HIV-1 infection

    The natural course of HIV-1 infection is widely variable with extremes of disease progression within 2 years (rapid progressors, RP) or continuous asymptomatic infection for more than 15 years (long term non progressors, LTNP). We have studied several reported polymorphisms in relation to HIV susceptibility and disease progression in the Amsterdam cohort. For example, a 32 base pair deletion in the CCR5 gene correlated with delayed disease progression, whereas a polymorphism in the tripartite interaction motif 5 gene (Trim5), that affects the antiviral activity of the Trim5a protein, was associated with an accelerated disease progression.

    Recently, a number of new host factors have been identified by our group in 1.) a genome wide single nucleotide polymorphism (SNP) analysis on associations with HIV-1 pathogenesis; 2.) genome wide SNP analysis on HIV-1 susceptibility of macrophages; 3.) genome wide transcriptional analysis of macrophages in association with HIV-1 susceptibility; and 4.) genome wide miRNA-analysis on HIV-1 susceptibility of macrophages. The identified host factors (HIV-1 dependency and restriction factors) are currently under study for their role in HIV-1 replication and HIV-1 pathogenesis.

    Viral hepatitis

    HBV is a small enveloped DNA virus belonging to the Hepadnaviridae group. It replicates through an intermediate RNA molecule that is reversely transcribed into a partially double-stranded circular DNA genome. The HBV-encoded polymerase is error prone, theoretically enabling the virus to quickly evolve under selection pressure, such as the adaptive immune response and antiviral therapy. This mechanism is limited by the fact that the HBV genome largely consists of overlapping genes. People with chronic HBV infection are at increased risk of developing liver cirrhosis and hepatocellular carcinoma. Current treatment of chronic HBV infection consists of nucleoside analogues, which inhibit virus replication at the step of reverse transcription, and interferon alpha, which has both an antiviral and immunomodulatory effect.

    HCV is a small enveloped single-stranded RNA virus belonging to the Flaviviridae family. Due to the high error rate of the viral RNA-dependent RNApolymerase, HCV has a high mutations rate and rapidly adapts to host immune responses and suboptimal treatment regiments. The current treatment for patients with HCV consist of combination therapy with interferon alpha, a nucleoside inhibitor and an HCV protease inhibitor. The success rate of the treatment is highly dependent on the HCV genotype and on the response to previous treatment. New insights in the HCV life cycle, has resulted in the development of many promising antiviral agents that interfere with HCV infection and replication. Some of these agents act directly on viral proteins, such as NS3/4A protease and NS5B RNA-dependent polymerase, whereas others target host factors that are essential for HCV replication, such as miR-122 or cyclophilin A.

    In collaboration with Prof. H. L. Zaaijer (Blood-borne Infections, Sanquin Amsterdam) and Dr. H. Reesink (Gastro-enterology Dept., AMC, Amsterdam), we study the role of viral and host factors (e.g. genetics and immunological) in viral replication and in response to antiviral therapy in chronic hepatitis patients. 

    Contact

    For further information please contact

    Dr. Neeltje Kootstra (Head LVIP)

    +31 (0)20 566 8298

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