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Understanding HIV Clades

How does the genetic diversity of HIV affect AIDS vaccine design?

A key concern for AIDS vaccine researchers is the tremendous genetic diversity of HIV. The majority of global HIV infections are caused by a single group of virus, which is divided into nine different subtypes, or clades, designated by the letters A through K. Further complicating matters are the viral recombinants that occur when viruses from different clades combine segments of their genome, forming a hybrid. These occur in several regions of the world where more than one HIV clade is circulating.

The advent of clades

The diversity of HIV and the development of clades stems from the ability of HIV to produce billions of viral particles daily. The enzyme involved in viral replication, reverse transcriptase, is not precise and sometimes incorporates mistakes into the viral genome, resulting in genetic mutations. The more HIV replicates, the more likely it is to make mistakes, increasing the potential for genetic variation.

Each of HIV's genes develops mutations at a different rate. The genetic sequence of the envelope gene (env), for example, which encodes the HIV surface protein that attaches the virus to human cells, can vary by as much as 35% in virus samples from different clades. Others, such as the gag gene that encodes the internal core of the virus, remain more conserved, varying by less than 10% from one clade to another. Overall, the genetic makeup between all clades deviates by approximately 30%.

HIV clades also vary in prevalence throughout the world. For example, HIV clade B is found mostly throughout North America and Europe, while the epidemic in South Africa and India is due to HIV clade C. Researchers are therefore trying to develop an AIDS vaccine candidate that offers the broadest possible protection.

But there are still many unanswered questions about the significance of viral diversity for AIDS vaccine design. Scientists do not yet know whether immune responses induced by a preventive AIDS vaccine would be able to protect against only one particular HIV clade or against several. Most clinical trials of AIDS vaccine candidates have occurred in communities where the antigen in the vaccine comes from the same HIV clade as the one circulating in the region, a concept known as clade or genetic matching. The key for an effective AIDS vaccine is to elicit the kind of immune response that would be effective against the circulating virus in the region, but this is not well predicted by clade alone. Clade classification refers to the different protein sequences that distinguish the circulating viruses and not the way the human immune system recognizes or reacts to HIV, so the importance of such matching is still in question. Scientists are also still trying to determine the type and magnitude of immune response required for protection, so clinical trials to determine the immunogenicity of vaccine candidates in relevant populations remain critical.

Implications for vaccine design

When the first AIDS vaccine trials were initiated, vaccine development efforts focused mostly on candidates from isolates of HIV clade B, found in North America, parts of South America, Western Europe, and Australia, and currently responsible for approximately 12% of global infections. Later, candidates with antigens from clades A and D, both common in parts of Africa, were brought to clinical trials. Several others were also developed based on clade C, the subtype circulating in Southern Africa, India, and China, which is responsible for over 50% of all HIV infections worldwide.

As more candidates entered clinical testing different approaches to vaccine development have emerged to tackle HIV diversity. One strategy aimed at eliciting cellular immune responses involves the use of the most conserved regions of HIV or widely recognized protein pieces from different parts of HIV to develop an AIDS vaccine candidate.

A different vaccine strategy that aims to elicit broadly-neutralizing antibodies against several clades uses a combination vaccine with env genes from several clades. A third approach, which is not yet in clinical trials, compares the sequences of HIV genomes from different clades to create a computer-generated sequence that best matches the highest number of strains, with the hope that any protective immune response that the vaccine elicits would confer protection against infection by different HIV clades.

Informing the field

Merck and the HIV Vaccine Trials Network (HVTN) are now completing site preparations in South Africa for a second Phase IIb "test of concept" trial with the company's clade B-based adenovirus serotype 5 (Ad5) vaccine candidate, known as MRKAd5. The candidate is currently being evaluated in another Phase IIb trial in North America, South America, the Caribbean, and Australia. The addition of a South African trial marks the first time this candidate will be evaluated in a population where the circulating clade of HIV, clade C, does not match that in the vaccine.

In 2003 the African AIDS Vaccine Programme came out strongly in favor of planning trials to give clear answers about protection across different clades as long as there is evidence that the vaccine candidate induces immune responses against the most commonly circulating virus, regardless of clade classification. Preclinical data for MRKAd5 show reactivity between the vaccine antigens and the predominant virus found in South Africa. The Merck trial therefore offers an opportunity to test this in a "proof of concept" trial that may provide preliminary answers about a vaccine's efficacy while answering crucial questions for vaccine design.