1. Human Health and Disease
Lecture 9

2. Immune system
The organs and processes of the body that provide resistance to infection and toxins.
Organs include the thymus, bone marrow, and lymph nodes.
The thymus gland, despite containing glandular tissue and producing several hormones, is much more closely associated with the immune system and serves a vital role in the differentiation and development of T-lymphocytes or T cells.
Lymph nodes are major sites of B, T, and other immune cells. Lymph nodes are important for the proper functioning of the immune system, acting as filters for foreign particles and cancer cells. Lymph nodes do not deal with toxicity, which is primarily dealt with by the liver and kidneys.

8. HIV life cycle

9. Inhibition of HIV

10. Inhibition of HIV
HIV binds to CD4 cell surface molecules, entry into the cell also requires binding to co-receptors CXCR4 and CCR5). This step can be inhibited by fusion/entry inhibitors.
HIV is uncoated inside the cell and reverse transcriptase copies genomic RNA into DNA, making errors at a frequence of about one per replication cycle. Reverse transcriptase inhibitors were the first class of HIV inhibitors to be used as drugs.
Viral DNA can integrate into DNA and become a part of the cellular genome. This step makes the infection irreversible, and may mean that eliminating the virus from an infected individual is not possible. Integrase inhibitors are designed to block this step of infection.
The virus uses cellular machinery to synthesize viral proteins. Several of these are long amino acid chains which must be cleaved by a specific viral protease before new viral particles can become active. Protease inhibitors block viral maturation at this step.

11. HAART
The drugs interfere with HIV replication at multiple steps as indicated above (integrase inhibitors in developmental stages only).
HAART or highly active anti-retroviral therapy with a combination of drugs results in a dramatic reduction in viral levels. HAART coupled with improved treatments of HIV caused secondary infections has dramatically improved survival for HIV infected patients.

12. HAART increases survival, but does not eliminate the virus
HAART increases survival, but does not eliminate the virus. CD4+ T cells maturing in the thymus can be infected and harbor virus indefinately. Virus levels rise rapidly if HAART is discontinued.
Immune function is significantly restored in treated individuals. However, the drug regime is difficult and accompanied by complications that may prevent continued treatments.
RNA viruses rapidly mutate. 10 billion HIV-1 virions are generated daily, with a rate giving one mutation for each new genome of 9,2000 nucleotides per replication cycle. Genomes with every possible mutation and many double mutations are generated daily. The rapidly changing virus makes therapy difficult.
Resistant virus emerges at high frequency.
Therapy is very expensive, and cannot be afforded by most countries with significant numbers of HIV infected people. Providing affordable drugs throughout the world remains a difficult goal for world health.

13. Vaccines
Vaccination to activate a long term immune response has erradicated small pox, and has nearly eliminated polio as a human disease. Major efforts are underway to develop HIV vaccines.
The obsticles are formidable. HIV replicates very rapidly, and errors in reverse transcription rapidly change the virus.
The ability of the virus to remain a part of the cellular genome, and become activated when cells of the immune system become active means that infected individuals harbor virus for the lifetime of a person.
A major problem is that HIV causes a vigorous immune response that affords some protection against the virus, but the process of protection can also activate virus replication and cause the disease to progress. We don't know what aspects of the immune response afford protection, and what steps cause progression. If these are different, it should be possible to increase protection and decrease progression. Studies of the immune system and HIV remain a very high priority.

14. Immuno therapy with lentiviral vector

15. Why HIV is a good candidate for gene therapy
web/Lentiviral/Lentivi2.html
therapy-tools-and-potential- applications/lentiviral-gene-therapy- vectors-challenges-and-future-directions
therapy-tools-and-potential- applications/targeted-lentiviral-vectors- current-applications-and-future-potential

16. Lentiviral vectors in Immunotherapy
therapy-tools-and-potential- applications/lentiviral-vectors-in- immunotherapy