Research Contents

  • How do HIV establish chronic infections in humans?
  • Why the human immune system fail to control HIV infection?

The majorities of the initial symptoms after the HIV infection are known, which in most cases resemble other viral infections such as influenza. However after infection, the infection remains in the body in life time. It is thought that HIV-1 is able escape from host immune system (such as acquired immunity and natural immunity) by using different mechanisms.

The lentivirus genus, such as HIV-1, has group of genes that are not found in other retroviruses. These are called accessory genes, in HIV-1(vif, vpr, vpu, nef ).  In contrast, some of these proteins are even different from HIV-2 which is closely related. Therefore, the structure of the accessory gene is thought to be related deeply with the nature of pathogenesis characteristic of the HIV-1.


 For example, HIV-1 Nef protein not only increases the replication capacity and infectivity of HIV-1 but also responsible for immune escape by mediating reduction of expression of HLA class I molecules which are involved in T-cell antigen recognition. In addition, very recently has been reported that the decreased expression of CD4 receptor by Nef is involved in the escape from the neutralizing antibody.  Encouraging the release of infectious virus particles by inhibiting the tetherin function (viral trap mechanism that human cells have) by Vpu has been reported. In addition, decreasing the expression of NK cell receptor by Nef has been shown to be involved in escape from the NK cell.

Analysis of infection in HIV-1 elite controllers

HIV-1 infected individuals who do not receive treatment with anti-HIV drugs, most of them will not be able to control HIV-1 and eventually become immunodeficiency. However on the other hand, about 0.5% (only a few infected people) able to spontaneously control HIV-1 infection and does not progress into AIDS for a long time in the absence of the HIV treatment; these infected individuals are called elite controllers. Study on how the human immune system of these individuals is able to control HIV-1 has been actively carried out. Our group has also investigated this unique group through a joint research with researchers from United States and Canada. Using 45 elite controller subjects, we have analyzed Nef gene protein function. We were able to identify some specific amino acid mutations that were found characteristically in the controller group; furthermore our findings revealed that many of these Nef protein variants have attenuated functions. Our elite controller study, it is the first study that showed Nef functions have been attenuated in HIV-1 controllers.



Analysis of Individual who become HIV-1 elite controllers

In the course of the HIV-1 infection, majority of the individual progress to AIDS due to failure to control HIV-1 infection without treatment. But some though few in number<1%> able to control such infection in absence of treatment and become elite controllers. Such infected individuals were possible to follow-up them over time, immediately just after infection to a point where they were able to stable control HIV-1 to undetectable level. We performed a detailed analysis so as to identify what is unique characteristic displayed by this controller group. In this analysis we found that reduced nef function was associated with relative control of initial viremia and the accumulation of the HLA-associated polymorphisms in acute stage were associated with impaired Nef function and hence immune control.


The immune response towards HIV-1 Vpu

Vpu is a protein that has a remarkable variability among the HIV-1 proteins. Although it is highly polymorphic, it is stably maintained as ORF suggesting its importance in infection and maintenance of viral replication in vivo. The factors that influence Vpu sequence polymorphisms are still not clearly defined; it is suggested that Vpu is a potential target for the immune system of the host, therefore may acquire sequence polymorphisms in order to avoid host mediated immune system. Given that HLA class I has been evidenced to drive sequence polymorphisms in other HIV-1 proteins such as Nef, we determined whether HLA class I alleles influence Vpu highly variable nature. We conducted Phylogenetic dependency network model analysis to determine Vpu amino acid mutations that are associated with HLA class I alleles. We observed a few number of Vpu mutations that are associated with HLA class I, suggesting that HLA class has a minor contribution in Vpu sequence polymorphism. In future it will be interesting to look more extensively on Vpu in order to determine the factors that influence polymorphisms in this protein.

The immune response towards HIV-1 Vpr