Replication Cycle of HIV in Human T Helper Cells

Most of the types of the viruses are host specific which means that they infects only a specific species. Similarly, HIV is host specific. Although, it can reside in the blood stream of chimpanzees, reproduce and divide but cannot cause infection in them. In case of humans, HIV is not only specific to host organism but specific to the cell type as well. The cells which are susceptible to HIV infection are T helper cells which are the major component of the human immune system. T helper cells bear CD4 receptors on their surface and CCR5 or CXCR4 as co-receptors. This makes the T helper cells vulnerable to HIV (Root-Bernstein, 2017). After a successful entry into the human bloodstream, HIV attacks T helper cells. Gp120 present on the envelope of the virus attaches to the CD4 receptors present on T helper cells. The transformational changes occur in the CD4 receptors allowing the attachment of gp120 with co-receptors CCR5 or CXCR4. Now gp41 peptide penetrates into CD4+ T cell membrane. Then gp41 collapses into hairpin-like structure that brings the virus and cell membrane of T helper cells closer together and subsequent entry of the viral capsid into the host cell. Then capsid is degraded and viral RNA is exposed. One of the viral RNA is degraded and the other one is reverse transcribed into double-stranded DNA by RT. This double-stranded viral DNA is called complementary DNA or cDNA. The transcription of ssRNA into cDNA is excessively error-prone and causes to produce many variants of HIV. Some of these variants happen to be drug resistant. The double-stranded cDNA newly produced by RT is transported into the host cell nucleus where it becomes the part of host cell genome by integrase. At this stage the integrated viral cDNA is called a provirus that may remain dormant for a long period of time. Alternatively, upon the activation of the T helper cells, NF-κB (nuclear factor kappa B) is upregulated. NF-κB is essential for actively producing virus (Dutta & Gupta, 2018). This means that virus cells start replicating in those T helper cells who have noticed the presence of provirus and going to fight against it. After that, viral genes are translated either into RNA for new viral progeny or into mRNA after splicing. In the cytoplasm, these mRNAs produce Tat and Rev proteins necessary for the production of the virus. Rev proteins move back to the nucleus and bind to the unspliced RNA helping them exiting the host nucleus and their subsequent entry into the newly formed viral particle. Gag proteins produced by spliced mRNA help the unspliced RNA to pack into a new viral particle that is to be budded off from the host cell (Lu et al., 2011). Gp160 goes through the endoplasmic reticulum and then through Golgi apparatus where it is cleaved into two env proteins i.e gp120 and gp41. Both these envelope glycoproteins goes to the plasma membrane of the HIV infected cells where gp41 embeds gp120 into the membrane. Gag polyproteins also assist this budding process. This immature budded virus eventually becomes matured when all the accessory proteins are packed into the virus. Complete HIV replication cycle has been shown in (Fig.1). The only mature virus is able to infect the other T helper cells. Hence, viral life cycle gets completed that has destroyed the helper T cells by taking its plasma membrane with them. When only 200 T cells per 1mm3 of the blood are left due to the prolonged HIV infection, the person is said to have AIDS (Pettit et al., 2018).

Fig.1 : Replication cycle of HIV in human T helper cells

Stages of HIV Infection

In most of the cases, HIV develops into its final stage knowns as AIDS. The reason behind this is no sign of the infection even after the four weeks of infection. (Fig. 4) shows the number of virus particles and decreasing number of T helper cells in the blood stream of the infected patient over the long period of time.

Acute Infection

After two to four weeks later to the HIV infection, the patient may develop influenza-like illness. This is often termed as acute HIV infection. The symptoms that occur in 40-90% of infected persons are throat inflammation, fever, headache, and tiredness, sores of the mouth and genitals, a rash, large tender lymph nodes. All these symptoms could be due to other seasonal changes or other pathogens, that is why at this stage it is extremely difficult to predict whether a patient is going to suffer from AIDS or not (Martin Vogel et al., 2010).

Clinical Latency

After 3-8 years of the infection, some people start to develop symptoms like weight loss, fever, muscle pains and gastrointestinal problems. 70% also develop persistent generalized lymphadenopathy which is characterized by enlargement of the lymph nodes in specific areas other than groin region.
HIV load is detectable at this stage and after the diagnosis of HIV clinical latency, antiretroviral therapy (ART) can be started. About 5% maintain high levels of CD4+ T cells without the implementation of ART. This group is called long-term non-progressors (LTNP). Some people have the capability to retain a very little viral load. These individuals are called elite controllers (Walker et al., 2015).

Acquired Immunodeficiency Syndrome

After 10 years of HIV infection with no proper treatment, AIDS develops. At this stage, the number of CD4 cells is less than 200 per 1mm3 of blood. Patients at this stage show cachexia in the form of HIV wasting syndrome (20%), pneumocystis pneumonia (40%), recurrent respiratory tract infections and oesophagal candidiasis.
Opportunistic infections also develop by the microorganisms like bacteria, fungi, parasites and other viruses. The infection mostly depends on the organism that is most common in the environment of the infected patient. These infections affect nearly every internal body organ (Martin Vogel et al., 2010).
AIDS patients may also develop virus-induced tumors and cancers such as cervical cancer, primary central nervous system lymphoma, Burkitt’s lymphoma and Kaposi’s sarcoma (M Vogel et al., 2011). Other common symptoms include sweats at night, fever for a longer period of time, swollen lymph nodes and diarrhoea. They may also start to suffer from neurological problems and diverse psychiatric issues independent of the tumors.(Martin Vogel et al., 2010) There are two ways to define whether you are suffering from AIDS or not. The first one is by calculating the number of CD4 T cells. Because HIV virus attacks helper T cell of the body, that is why it causes a decrease in the number of these T cells. If the number of cells reached to only equal to or less than 200 T cell per mm3 of the blood as compared to the normal body CD4 cell count 500 – 1500 cells per mm3 of the blood, the patient is said to suffer from AIDS (Dutta & Gupta, 2018). The second method to define whether the person is suffering from AIDS or not, is to see the AIDS-defining opportunistic infections.

Fig.2 : Different stages of HIV infection leading to the development of AIDS